Oxo-purines as angiotensin II antagonists

ABSTRACT

Substituted Imidazo-fused 6-membered heterocycles of structural formula:    &lt;IMAGE&gt;  (I)  wherein A, B, C, and D are independently carbon atoms or nitrogen atoms are angiotensin II antagonists useful in the treatment of hypertension and congestive heart failure.

SUMMARY OF THE INVENTION

This is a division of application Ser. No. 07/516,286, filed May 4,1990, which is a continuation-in-part of copending application Ser. No.358,971 filed May 30, 1989 now abandoned.

This invention relates to novel compounds of structural formula I whichare angiotensin II antagonists useful in the treatment of hypertension,congestive heart failure, and elevated intraocular pressure.

It also relates to processes for preparing the novel compounds;pharmaceutical formulations comprising one or more of the compounds asactive ingredient; and, a method of treatment of hypertension,congestive heart failure, and elevated intraocular pressure.

BACKGROUND OF THE INVENTION

Renin-angiotensin system (RAS) plays a central role in the regulation ofnormal blood pressure and seems to be critically involved inhypertension development and maintenance as well as congestive heartfailure. Angiotensin II (AII), an octapeptide hormone is produced mainlyin the blood during the cleavage of angiotensin I by angiotensinconverting enzyme (ACE) localized on the endothelium of blood vessels oflung, kidney, and many other organs, and is the end product of the RAS.AII is a powerful arterial vasoconstricter that exerts its action byinteracting with specific receptors present on cell membranes. One ofthe possible modes of controlling the RAS is angiotensin II receptorantagonism. Several peptide analogs of A II are known to inhibit theeffect of this hormone by competitively blocking the receptors, buttheir experimental and clinical applications have been limited by thepartial agonist activity and lack of oral absorption [M. Antonaccio.Clin. Exp. Hypertens. A4, 27-46 (1982); D. H. P. Streeten and G. H.Anderson, Jr. --Handbook of Hypertension, Clinical Pharmacology ofAntihypertensive Drugs, ed. A. E. Doyle, Vol. 5, pp. 246-271, ElsevierScience Publisher, Amsterdam, The Netherlands, 1984].

Recently, several non-peptide compounds have been described as A IIantagonists. Illustrative of such compounds are those disclosed in U.S.Pat. Nos. 4,207,324; 4,340,598; 4,576,958; 4,582,847; and 4,880,804; inEuropean Patent Applications 028,834; 245,637; 253,310; and 291,969; andin articles by A. T. Chiu, et al. [Eur. J. Pharm. Exp. Therap, 157,13-21 (1988)] and by P. C. Wong, et al. [J. Pharm. Exp. Therap, 247, 1-7(1988)]. All of the U.S. Patents, European Patent Applications 028,834and 253,310 and the two articles disclose substituted imidazolecompounds which are generally bonded through a lower alkyl bridge to asubstituted phenyl. European Patent Application 245,637 disclosesderivatives of4,5,6,7-tetrahydro-2H-imidazo[4,5-c]-pyridine-6-carboxylic acid andanalogs thereof as antihypertensive agents.

None of the compounds disclosed in the above identified U.S. Patents,European Applications and articles have the heterobicyclic structure ofthe compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to substituted imidazo-fused 6-membered ringheterocycles of the formula I shown below which are angiotensin IIantagonists and are useful in the treatment of hypertension, congestiveheart failure, and elevated intraocular pressure. ##STR2## wherein: R¹is

(a) --CO₂ R⁴,

(b) --SO₃ R⁵,

(c) --NHSO₂ CF₃,

(d) --PO(OR⁵)₂,

(e) --SO₂ --NH--R⁹,

(f) --CONHOR⁵,

(g) ##STR3## (h) --SO₂ NH-heteroaryl, (i) --CH₂ SO₂ NH-heteroaryl,

(j) --SO₂ NHCO--R²³,

(k) --CH₂ SO₂ NHCO--R²³,

(l) --CONH--SO₂ R²³,

(m) --CH₂ CONH--SO₂ R²³,

(n) --NHSO₂ NHCO--R²³,

(o) --NHCONHSO₂ --R²³,

(p) --SO₂ NHCONR²³,

(q) ##STR4## (r) ##STR5## (s) ##STR6## (t) --CONHNHSO₂ CF₃, (u) ##STR7##(v) ##STR8## (w) ##STR9## wherein heteroaryl is an unsubstituted,monosubstituted or disubstituted five- or six-membered aromatic ringwhich can optionally contain 1 to 3 heteroatoms selected from the groupconsisting of O, N or S and wherein the substituents are membersselected from the group consisting of --OH, --SH, --C₁ -C₄ -alkyl, --C₁-C₄ -alkoxy, halo(Cl, Br, F, I), --NO₂, --CO₂ H, --CO₂ --C₁ -C₄ -alkyl,--NH₂, --NH(C₁ -C₄ -alkyl) and --N(C₁ -C₄ -alkyl)₂ ;

R^(2a) and R^(2b) are independently H, halo(Cl, Br, I, F), --NO₂, --NH₂,C₁ -C₄ -alkylamino, di(C₁ -C₄ alkyl)amino, --SO₂ NHR⁹, CF₃, C₁ -C₄-alkyl, or C₁ -C₄ -alkoxy;

R^(3a) is

(a) H,

(b) halo(Cl, Br, I, F)

(c) C₁ -C₆ -alkyl,

(d) C₁ -C₆ -alkoxy,

(e) C₁ -C₆ -alkoxyalkyl;

R^(3b) is

(a) H,

(b) halo (Cl, Br, I, F)

(c) NO₂,

(d) C₁ -C₆ -alkyl,

(e) C₁ -C₆ -acyloxy,

(f) C₁ -C₆ -cycloalkyl

(g) C₁ -C₆ -alkoxy,

(h) --NHSO₂ R⁴,

(i) hydroxy C₁ -C₄ -alkyl,

(j) aryl C₁ -C₄ -alkyl

(k) C₁ -C₄ -alkylthio

(l) C₁ -C₄ -alkyl sulfinyl

(m) C₁ -C₄ -alkyl sulfonyl

(n) NH₂

(o) C₁ -C₄ -alkylamino

(p) C₁ -C₄ -dialkylamino

(q) fluoro C₁ -C₄ -alkyl

(r) --SO₂ --NHR⁹

(s) aryl or,

(t) furyl;

wherein aryl is phenyl or naphthyl optionally substituted with one ortwo substituents selected from the group consisting of halo(Cl, Br, I,F), C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, NO₂, CF₃, C₁ -C₄ -alkylthio, OH, NH₂,NH(C₁ -C₄ -alkyl), N(C₁ -C₄ -alkyl)₂, CO₂ H, and CO₂ --C₁ -C₄ -alkyl;

R⁴ is H, straight chain or branched C₁ -C₆ alkyl, aryl or --CH₂ -arylwhere aryl is as defined above;

R^(4a) is C₁ -C₆ -alkyl, aryl or --CH₂ -aryl where aryl is as definedabove;

R⁵ is H, ##STR10## E is a single bond, --NR¹³ (CH₂)_(s) --, --S(O)_(x)--(CH₂)_(s) -- where x is 0 to 2 and s is 0 to 5, --CH(OH)--, --O--,--CO--;

R⁶ is

(a) aryl as defined above optionally substituted with 1 or 2substituents selected from the group consisting of halo (Cl, Br, I, F)--O--C₁ -C₄ -alkyl, C₁ -C₄ -alkyl, --NO₂, --CF₃, --SO₂ NR⁹ R¹⁰, --S--C₁-C₄ -alkyl, --OH, --NH₂, C₃ -C₇ -cycloalkyl, C₃ -C₁₀ -alkenyl;

(b) straight chain or branched C₁ -C₉ -alkyl, C₂ -C₆ -alkenyl or C₂ -C₆-alkynyl each of which can be optionally substituted with a substituentselected from the group consisting of aryl as defined above, C₃ -C₇-cycloalkyl, halo (Cl, Br, I, F) --OH, --NH₂, --NH(C₁ -C₄ -alkyl), --CF₂CF₃, --N(C₁ -C₄ -alkyl)₂, --NH--SO₂ R⁴, --COOR⁴, --CF₃, --CF₂ CH₃, --SO₂NHR⁹ ; or

(c) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6membered cyclic ring which can contain one or two members selected fromthe group consisting of N, O, S, and wherein the substituents aremembers selected from the group consisting of --OH, --SH, C₁ -C₄ -alkyl,C₁ -C₄ -alkyloxy, --CF₃, halo (Cl, Br, I, F), or NO₂,

(d) perfluoro-C₁ -C₄ -alkyl,

(e) C₃ -C₇ -cycloalkyl optionally mono- or disubstituted with C₁ -C₄-alkyl or --CF₃ ;

R⁹ is H, C₁ -C₅ -alkyl, aryl or --CH₂ -aryl where aryl is as definedabove;

R¹⁰ is H, C₁ -C₄ -alkyl;

R¹¹ is H, C₁ -C₆ -alkyl, C₂ -C₄ -alkenyl, C₁ -C₄ -alkoxy-C₁ -C₄ -alkyl,or ##STR11## R¹² is --CN, --NO₂ or --CO₂ R⁴ ; R¹³ is H, --CO(C₁ -C₄-alkyl), C₁ -C₆ -alkyl, allyl, C₃ -C₆ -cycloalkyl, phenyl or benzyl;

R¹⁴ is H, C₁ -C₈ -alkyl, C₁ -C₈ -perfluoroalkyl, C₃ -C₆ -cycloalkyl,phenyl or benzyl;

R¹⁵ is H, C₁ -C₆ -alkyl;

R¹⁶ is H, C₁ -C₆ -alkyl, C₃ -C₆ -cycloalkyl, phenyl or benzyl;

R¹⁷ is --NR⁹ R¹⁰, --OR¹⁰, --NHCONH₂, --NHCSNH₂, ##STR12## R¹⁸ and R¹⁹are independently C₁ -C₄ -alkyl or taken together are --(CH₂)_(q) -where q is 2 or 3;

R²⁰ is H, --NO₂, --NH₂, --OH or --OCH₃ ;

R²³ is

(a) aryl as defined above,

(b) heteroaryl as defined above,

(c) C₃ -C₄ -cycloalkyl,

(d) C₁ -C₄ -alkyl which can be optionally substituted with a substituentthat is a member selected from the group consisting of aryl as definedabove, heteroaryl as defined above, --OH, --SH, --C₁ -C₄ -alkyl, --O(C₁-C₄ -alkyl), --S(C₁ -C₄ -alkyl), --CF₃, halo(Cl, Br, F, I), --NO₂, --CO₂H, --CO₂ --C₁ -C₄ -alkyl, --NH₂, --NH(C₁ -C₄ -alkyl), --NHCOR^(4a),--N(C₁ -C₄ -alkyl)₂, --PO₃ H, --PO(OH)(C₁ -C₄ -alkyl), --PO(OH)(aryl),or --PO(OH)(O--C₁ -C₄ -alkyl),

(e) perfluoro-C₁ -C₄ -alkyl;

X is absent or is

(a) a carbon-carbon single bond,

(b) --CO--,

(c) --O--,

(d) --S--,

(e) ##STR13## (f) ##STR14## (g) ##STR15## (h) --OCH₂ --, (i) --CH₂ O--

(j) --SCH₂ --,

(k) --CH₂ S--,

(l) --NHC(R⁹)(R¹⁰),

(m) --NR⁹ SO₂ --,

(n) --SO₂ NR⁹ --,

(o) --C(R⁹)(R¹⁰)NH--,

(p) --CH═CH--,

(q) --CF═CF--,

(r) --CH═CF--,

(s) --CF═CH--,

(t) --CH₂ CH₂ --,

(u) --CF₂ CF₂ --,

(v) ##STR16## (w) ##STR17## (x) ##STR18## (y) ##STR19## or (z) ##STR20##Z is O, NR¹³ or S; --A--B--C--D-- represents the constituent atoms of a6-member saturated or unsaturated heterocyclic ring with the imidazoleto which they are attached containing 1 to 3 nitrogen atoms and includesthe following: ##STR21## wherein: R⁷ groups can be the same or differentand represent:

a) hydrogen,

b) C₁ -C₆ straight or branched chain alkyl, or C₂ -C₆ alkenyl, oralkynyl each of which is unsubstituted or substituted with:

i) --OH

ii) C₁ -C₄ -alkoxy,

iii) --CO₂ R⁴,

iv) --OCOR⁴,

v) ##STR22## vi) --CON(R⁴)₂ vii) ##STR23## viii) --N(R⁴)₂, ix) aryl asdefined above,

x) heterocyclic as defined in (o) below,

xi) --S(O)_(x) R²³,

xii) tetrazol-5-yl,

xiii) --CONHSO₂ R²³,

xiv) --SO₂ NH-heteroaryl,

xv) --SO₂ NHCOR²³,

xvi) ##STR24## xvii) ##STR25## xviii) ##STR26## xix) --PO(OR⁴)₂, xx)--PO(OR⁴)R⁹,

c) halo, such as chloro, bromo or iodo,

d) perfluoro-C₁ -C₄ -alkyl,

e) --OH,

f) --NH₂,

g) ##STR27## h) ##STR28## i) --OR²³, j) --CO₂ R⁴,

k) --CON(R⁴)₂,

l) --NH--C₃ -C₇ -cycloalkyl,

m) C₃ -C₇ -cycloalkyl,

n) aryl as defined above, or

o) heterocyclic which is a five- or six- membered saturated orunsaturated ring containing up to three heteroatoms selected from thegroup consisting of O, N or S wherein S may in the form of sulfoxide orsulfone and which may be optionally substituted with one or twosubstituents which are members selected from the group consisting ofhalo (Cl, Br; F, I), C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ --S(O)_(x)--where x is as defined above, CF₃, NO₂, OH, CO₂ H, CO₂ --C₁ -C₄ -alkyl,or --N(R⁴)₂ ;

p) --CN,

q) ##STR29## wherein n is 4 to 6, r) --SO₂ N(R⁴)₂ ;

s) tetrazol-5-yl,

t) --CONHSO₂ R²³,

u) --PO(OR⁴)₂,

v) --NHSO₂ CF₃,

w) --SO₂ NH-heteroaryl,

x) --SO₂ NHCOR²³,

y) --S(O)_(x) -R²³,

z) ##STR30## aa) --PO(OR⁴)R⁹, bb) --NHSO₂ R²³,

cc) --NHSO₂ NHR²³,

dd) --NHSO₂ NHCOR²³,

ee) --NHCONHSO₂ R²³,

ff) --N(R⁴)CO₂ R²³,

gg) ##STR31## hh) --CO--aryl, ii) ##STR32## jj) --CO--C₁ -C₄ -alkyl, kk)--SO₂ NH--CN,

ll) ##STR33## mm) ##STR34## R⁸ groups can be the same or different andrepresent: a) hydrogen,

b) C₁ -C₆ -alkyl or alkenyl either unsubstituted or substituted withhydroxy, C₁ -C₄ -alkoxy, --N(R⁴)₂, --CO₂ R⁴, or C₃ -C₅ -cycloalkyl;

c) C₃ -C₅ -cycloalkyl,

R^(8a) is R⁸ or C₁ -C₄ -acyl;

R^(9a) groups can be the same or different and represent:

a) hydrogen,

b) C₁ -C₆ -alkyl either unsubstituted or substituted with

i) hydroxy,

ii) --CO₂ R⁴,

iii) --CONHR⁴, or

iv) --CON(R⁴)₂ ; and,

the pharmaceutically acceptable salts thereof.

One embodiment of the novel compounds of this invention is the classcompounds of Formula I wherein:

R¹ is:

a) --CO₂ R⁴

b) --NHSO₂ CF₃

c) ##STR35## d) ##STR36## (e) --SO₂ NH-heteroaryl, (f) --CH₂ SO₂NH-heteroaryl,

(g) --SO₂ NHCOR²³,

(h) --CH₂ SO₂ NHCOR²³,

(i) --CONHSO₂ R²³,

(j) --CH₂ CONHSO₂ R²³,

(k) --NHSO₂ NHCOR²³, or

(l) --NHCONHSO₂ R²³,

(m) --SO₂ NHCONHR²³,

wherein heteroaryl is as first defined above;

X is a single bond;

R^(2a) and R^(2b) are independently:

a) C₁ -C₄ -alkyl,

b) halogen,

c) hydrogen;

R^(3a) and R^(3b) are independently:

a) C₁ -C₆ -alkyl,

b) halogen, or

c) C₁ -C₆ -alkoxy,

d) hydrogen;

R⁴ is H, or C₁ -C₄ -alkyl;

E is a single bond or --S--;

R⁶ is a branched or straight chain C₁ -C₆ -alkyl, C₃ -C₇ -cycloalkyl, C₂-C₆ -alkenyl or C₂ -C₆ -alkynyl each of which is either unsubstituted orsubstituted with C₁ -C₄ -alkylthio, C₁ -C₄ -alkoxy, CF₃, CF₂ CF₃ or--CF₂ CH₃ ;

and A--B--C--D-- represents: ##STR37## wherein R⁷ groups are the same ordifferent and represent:

a) hydrogen,

b) --C₁ -C₄ -alkyl, either unsubstituted or substituted with:

i) --OH,

ii) --CO₂ R⁴,

iii) --NH₂,

iv) (C₁ -C₄ alkyl)amino,

v) di(C₁ -C₄ -alkyl)amino,

c) halo,

d) --CF₃,

e) --OH,

f) --N(R⁴)₂,

g) --C₁ -C₄ -alkoxy,

h) --CO₂ R⁴,

i) --CONH₂,

j) --C₃ -C₇ -cycloalkyl,

k) aryl,

l) heterocyclic as defined above,

m) --CF₃,

n) tetrazol-5-yl,

o) --CONHSO₂ R²³ ;

R⁸ groups are the same or different and represent,

a) hydrogen,

b) C₁ -C₄ -alkyl either unsubstituted or substituted with --OH or --CO₂R⁴ ; and

R^(8a) represents

a) hydrogen,

b) C₁ -C₄ alkyl, or

c) (C₁ -C₄ -alkyl)CO--; and

R^(9a) groups are the same or different and represent:

a) hydrogen,

b) C₁ -C₄ -alkyl.

Another embodiment of this invention is the group of compounds ofFormula I wherein:

R¹ is:

a) --CO₂ R⁴,

b) --SO₂ NH-heteroaryl,

c) --CH₂ SO₂ NH-heteroaryl,

d) --SO₂ NHCOR²³,

e) --CH₂ SO₂ NHCOR²³,

f) --CONHSO₂ R²³,

g) --CH₂ CONHSO₂ R²³,

h) --NHSO₂ NHCOR²³,

i) --NHCONHSO₂ R²³,

j) --SO₂ NHCONHR²³,

k) ##STR38## or l) --NHSO₂ CF₃,

wherein heteroaryl is as first defined above;

R^(2a) and R^(2b) are independently:

a) C₁ -C₄ -alkyl, or

b) chloro,

c) hydrogen;

R^(3a) and R^(3b) are independently:

a) C₁ -C₄ -alkyl,

b) chloro, or

c) C₁ -C₄ -alkoxy,

d) hydrogen;

E is a single bond or --S--;

R⁶ is

(a) a branched or straight chain C₁ -C₆ -alkyl, C₂ -C₆ -alkenyl or C₂-C₆ -alkynyl each of which is either unsubstituted or substituted withC₁ -C₄ -alkylthio, C₁ -C₄ -alkoxy, CF₃, CF₂ CF₃ or --CF₂ CH₃ ;

(b) C₃ -C₇ -cycloalkyl;

(c) perfluoro-C₁ -C₄ -alkyl;

A--B--C--D-- represents: ##STR39## wherein R⁷ groups are the same ordifferent and represent:

a) hydrogen,

b) --C₁ -C₄ -alkyl, either unsubstituted or substituted with --OH or--CO₂ R⁴,

c) halo,

d) --OH,

e) --N(R⁴)₂,

f) --C₁ -C₄ -alkoxy, or

g) --CO₂ R⁴,

h) aryl,

i) heterocyclic as defined above,

j) --CF₃,

k) tetrazol-5-yl,

R⁸ groups are the same or different and represent:

a) H,

b) C₁ -C₄ -alkyl either unsubstituted or substituted with --OH or --CO₂R⁴.

In a class of this embodiment are those compounds of Formula I wherein:

R¹ is

a) --CO₂ R⁴

b) ##STR40## c) --NHSO₂ CF₃, d) --SO₂ NH-heteroaryl,

e) --CH₂ SO₂ NH-heteroaryl,

f) --SO₂ NHCOR²³,

g) --CH₂ SO₂ NHCOR²³,

h) --CONHSO₂ R²³,

i) --CH₂ CONHSO₂ R²³ ;

E is a single bond;

A--B--C--D represents: ##STR41##

Exemplifying this class are the following compounds:

(1) 2-Butyl-3-(2'-carboxybiphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(2) 3-(2'-Carboxybiphen-4-yl)methyl-2-propyl-3H-imidazo[4,5-b]pyridine;

(3) 3-(2'-Carboxybiphen-4-yl)methyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(4)3-(2'-Carboxybiphen-4-yl)methyl-2-isopropyl-3H-imidazo[4,5-b]pyridine;

(5)3-(2'-Carboxybiphen-4-yl)methyl-2-cyclopropyl-3H-imidazo[4,5-b]pyridine;

(6)3-(2'-Carboxybiphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine;

(7)3-(2'-Carboxybiphen-4-yl)methyl-7-ethyl-2-propyl-3H-imidazo[4,5-b]pyridine;

(8)3-(2'-Carboxybiphen-4-yl)methyl-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine;

(9)3-(2'-Carboxybiphen-4-yl)methyl-2,7-diethyl-3H-imidazo[4,5-b]pyridine;

(10)3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine;

(11)3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(12)3-(2'-Carboxybiphen-4-yl)methyl-2-cyclopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

(13)3-(2'-Carboxybiphen-4-yl)methyl-5-ethyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine;

(14)3-(2'-Carboxybiphen-4-yl)methyl-2,5-diethyl-7-methyl-3H-imidazo[4,5-b]pyridine;

(15)3-(2'-Carboxybiphen-4-yl)methyl-2-ethyl-7-methyl-5-methylamino-3H-imidazo[4,5-b]pyridine;

(16)5-Amino-3-(2'-carboxybiphen-4-yl)methyl-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine;

(17)3-(2'-Carboxybiphen-4-yl)methyl-2-ethyl-5-methylamino-7-trifluoromethyl-3H-imidazo[4,5-b]pyridine;

(18)3-(2'-Carboxybiphen-4-yl)methyl-2-ethyl-5-methyl-7-methylamino-3H-imidazo[4,5-b]pyridine;

(19)3-(2'-Carboxybiphen-4-yl)methyl-7-dimethylamino-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine;

(20)3-(2'-Carboxybiphen-4-yl)methyl-2-ethyl-5-methyl-7-phenylamino-3H-imidazo[4,5-b]pyridine;

(21)3-(2'-Carboxybiphen-4-yl)methyl-2-ethyl-5-methyl-7-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine;

(22)3-(2'-Carboxybiphen-4-yl)methyl-2-ethyl-7-methyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine;

(23)3-(2'-Carboxybiphen-4-yl)methyl-2-ethyl-7-methoxy-5-methyl-3H-imidazo[4,5-b]pyridine;

(24)3-(2'-Carboxybiphen-4-yl)methyl-2-ethyl-5-hydroxymethyl-7-methyl-3H-imidazo[4,5-b]pyridine;

(25)5-Carboxy-3-(2'-carboxybiphen-4-yl)methyl-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine;

(26)5-Carbomethoxy-3-(2'-carboxybiphen-4-yl)methyl-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine;

(27)3-(2'-Carboxybiphen-4-yl)methyl-2-ethyl-7-methyl-5-phenyl-3H-imidazo[4,5-b]pyridine;

(28)3-(2'-Carboxybiphen-4-yl)methyl-5-(2-chloro)phenyl-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine;

(29)3-(2'-Carboxybiphen-4-yl)methyl-5-(4-chloro)phenyl-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine;

(30)3-(2'-Carboxybiphen-4-yl)methyl-2-ethyl-7-methyl-5-(2-trifluoromethyl)phenyl-3H-imidazo[4,5-b]pyridine;

(31)6-Amino-3-(2'-carboxybiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(32)3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-6-ethylamino-3H-imidazo[4,5-b]pyridine;

(33)3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-6-fluoro-3H-imidazo[4,5-b]pyridine;

(34) 3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-(2,2,2,-trifluoro)ethyl-3H-imidazo[4,5-b]pyridine;

(35)3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-pentafluoroethyl-3H-imidazo[4,5-b]pyridine;

(36)3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-(3,3,3,-trifluoro)propyl-3H-imidazo[4,5-b]pyridine;

(37)3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-(4,4,4,-trifluoro)butyl-3H-imidazo[4,5-b]pyridine;

(38) 3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-(2,2,-difluoro)propyl-3H-imidazo[4,5-b]pyridine;

(39)3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-(trans-2-butenyl)-3H-imidazo[4,5-b]pyridine;

(40)3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-(trans-1-propenyl)-3H-imidazo[4,5-b]pyridine;

(41)2-Allyl-3-(2'-carboxybiphen-4-yl)methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

(42)3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-(2-propynyl)-3H-imidazo[4,5-b]pyridine;

(43)2-(2-Butynyl)-3-(2'-carboxybiphen-4-yl)methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;

(44)3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-(4,4,4-trifluoro-2-butynyl)-3H-imidazo[4,5-b]pyridine;

(45)3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-(2,2,2-trifluro)ethoxy-3H-imidazo[4,5-b]pyridine;

(46)2-Butyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)-methyl-3H-imidazo[4,5-b]pyridine;

(47)2-Propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(48)2-Ethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(49)2-Isopropyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(50)2-Cyclopropyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(51)2-Butyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(52)7-Methyl-2-(3-methyl)propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(53)2-Methoxymethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(54)7-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(55)7-Ethyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(56)2-Ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(57)2,7-Diethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(58)2-Butyl-5,7-dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(59)5,7-Dimethyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(60)5,7-Dimethyl-2-ethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(61)2-Cyclopropyl-5,7-dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(62)5-Ethyl-7-methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(63)2,5-Diethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(64)2,7-Dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(65)7-Methyl-2-pentyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(66)7-Methyl-2-nonyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(67)2-Ethyl-7-methyl-5-methylamino-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(68)5-Amino-7-methyl-2-ethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(69)5-Amino-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(70)2-Ethyl-5-methylamino-7-trifluoromethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(71)2-Ethyl-5-methyl-7-methylamino-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(72)7-Dimethylamino-2-ethyl-5-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(73)2-Ethyl-5-methyl-7-phenylamino-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(74)2-Ethyl-5-methyl-7-(morpholin-4-yl)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(75)2-Ethyl-7-methyl-5-(morpholin-4-yl)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(76)5-Amino-2-ethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-7-trifluoromethyl-3H-imidazo[4,5-b]pyridine;

(77)2-Ethyl-7-methoxy-5-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(78)2-Ethyl-5-hydroxymethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(79)5-Carboxy-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(80)5-Carbomethoxy-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(81)2-Ethyl-7-methyl-5-phenyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(82)5-(2-Chloro)phenyl-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(83)5-(4-Chloro)phenyl-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(84)2-Ethyl-7-methyl-5-(2-trifluoromethyl)phenyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5b]pyridine;

(85)6-Amino-5,7-dimethyl-2-ethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(86)5,7-Dimethyl-2-ethyl-6-ethylamino-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(87)5,7-Dimethyl-2-ethyl-6-fluoro-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(88)5,7-Dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-2-(2,2,2,-trifluoro)ethyl-3H-imidazo[4,5-b]pyridine;

(89)5,7-Dimethyl-2-pentafluoroethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(90)5,7-Dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-2-(3,3,3,-trifluoro)propyl-3H-imidazo[4,5-b]pyridine;

(91)5,7-Dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-2-(4,4,4,-trifluoro)butyl-3H-imidazo[4,5-b]pyridine;

(92)5,7-Dimethyl-2-(2,2,-difluoro)propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(93)5,7-Dimethyl-2-(trans-2-butenyl)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(94)5,7-Dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-2-(trans-1-propenyl)-3H-imidazo[4,5-b]pyridine;

(95)2-Allyl-5,7-dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(96)5,7-Dimethyl-2-(2-propynyl)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(97)2-(2-Butynyl)-5,7-dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(98)5,7-Dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-2-(4,4,4-trifluoro-2-butynyl)-3H-imidazo[4,5-b]pyridine;

(99)5,7-Dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-2-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine;

(100)5,7-Dimethyl-2-ethyl-3-(2'-(N-((phenylsulfonyl)carboxamido)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(101)5,7-Dimethyl-2-ethyl-3(2'-(N-(2-bromophenylsulfonyl)carboxamido)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(102)3-(2'-(N-(4-Chlorophenylsulfonyl)carboxamido)biphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine;

(103)3-(2'-(N-Methylsulfonylcarboxamido)biphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine;

(104)5,7-Dimethyl-2-ethyl-3-(2'-(N-methylsulfonyl)carboxamidobiphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(105)5,7-Dimethyl-2-ethyl-3-(2'-(N-trifluoromethylsulfonyl)carboxamidobiphen-4-yl)methyl-3H-imidazo-[4,5-b]pyridine;

(106)3-(2'-(N-(2-Aminoethyl)sulfonyl)carboxamidobiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(107)5,7-Dimethyl-2-ethyl-3-(2'-(N-(morpholin-4-yl)sulfonyl)carboxamidobiphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(108)5,7-Dimethyl-(2'-(N-(N,N-dimethylamino)sulfonyl)carboxamidobiphen-4-yl)methyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(109)3-(2'-(N-Cyclopentylsulfonyl)carboxamidobiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(110)5,7-Dimethyl-2-ethyl-3-(2'-(N-pyrimidin-2-yl)sulfonamidobiphen-4-yl)methyl-3H-imidazo-[4,5-b]pyridine;

(111)5,7-Dimethyl-3-(2'-(N-(4,6-dimethylpyrimidin-2-yl)sulfonamido)biphen-4-yl)methyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(112)5,7-Dimethyl-2-ethyl-3-(2'-(N-(triazin-2-yl)sulfonamido)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(113)5,7-Dimethyl-2-ethyl-3-(2'-(N-(oxazol-2-yl)sulfonamido)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(114)3-(2'-(N-Acetyl)sulfonamidobiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(115)3-(2'-(N-Benzoyl)sulfonamidobiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(116)5,7-Dimethyl-2-ethyl-3-(2'-(N-(4-nitro)benzoyl)sulfonamidobiphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(117)3-(2'-(N-(4-Chloro)benzoyl)sulfonamidobiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(118)5,7-Dimethyl-2-ethyl-3-(2'-(N-(morpholin-4-yl)carbonyl)sulfonamidobiphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(119)5,7-Dimethyl-2-ethyl-3-(2'-(N-(piperazin-1-yl)carbonyl)sulfonamidobiphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(120)5,7-Dimethyl-2-ethyl-3-(2'-(N-(trifluoromethyl)carbonyl)sulfonamidobiphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(121)3-(2'-(N-(2-Carboxyethyl)carbonyl)sulfonamidobiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(122)5,7-Dimethyl-3-(2'-(N-(2'-ethoxyethyl)carbonyl)sulfonamidobiphen-4-yl)methyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(123)5,7-Dimethyl-2-ethyl-3-(2'-(N-(phenylsulfonyl)carboxamidomethyl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(124)5,7-Dimethyl-3-(2'-N-(4,6-dimethylpyrimidin-2-yl)sulfamidomethyl)biphen-4-yl)methyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(125)7-Methyl-3-(2'-(N-phenylsulfonyl)carboxamidobiphen-4-yl)methyl-2-propyl-3H-imidazo[4,5-b]pyridine;

(126)3-(2'-((N-Acetyl)sulfonamidomethyl)biphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine;

(127)7-Methyl-2-propyl-3-((2'-trifluoromethanesulfonylamino)bipheny-4-yl)methyl-3H-imidazopyridine;

(128)5,7-Dimethyl-2-ethyl-3-((2'-trifluoromethanesulfonylamino)biphen-4-yl)methyl-3H-imidazopyridine;

(129)4,7-Dimethyl-2-ethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyrid-5-one;

(130)2-Ethyl-5-hydroxy-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(131)7-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridinesodium salt;

(132)7-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridinepotassium salt;

(133)5,7-Dimethyl-2-ethyl-3-(4'-chloro-2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(134)5,7-Dimethyl-2-ethyl-3-(4'-fluoro-2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(135)5,7-Dimethyl-2-ethyl-3-(4'-amino-2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(136)5,7-Dimethyl-2-ethyl-3-(5'-fluoro-2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(137)3-(2'-Carboxy-6'-chlorobiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

(138)3-(2'-Carboxy-3'-fluorobiphen-4-yl)methyl-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine;

(139)5,7-Dimethyl-2-ethyl-3-(4'-nitro-2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine;

(140)5,7-Dimethyl-2-ethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridinesodium salt;

(141)5,7-Dimethyl-2-ethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridinepotassium salt;

(142) 9-(2'-Carboxybiphen-4-yl)methyl-6-chloro-8-propylpurine;

(143) 9-(2'-Carboxybiphen-4-yl)methyl-6-methyl-8-propylpurine;

(144) 9-(2'-Carboxybiphen-4-yl)methyl-6-methyl-8-ethylpurine;

(145) 9-(2'-Carboxybiphen-4-yl)methyl-4,6-dimethyl-8-propylpurine;

(146) 9-(2'-Carboxybiphen-4-yl)methyl-4,6-dimethyl-8-ethylpurine;

(147)9-(2'-Carboxybiphen-4-yl)methyl-4-dimethylamino-6-methyl-8-ethylpurine;

(148)9-(2'-Carboxybiphen-4-yl)methyl-4-methylamino-6-methyl-8-ethylpurine;

(149)9-(2'-Carboxybiphen-4-yl)methyl-4-(morpholin-4-yl)-6-methyl-8-ethylpurine;

(150)9-(2'-Carboxybiphen-4-yl)methyl-4-ethylamino-6-methyl-8-ethylpurine;

(151)9-(2'-Carboxybiphen-4-yl)methyl-4-propylamino-6-methyl-8-ethylpurine;

(152)9-(2'-carboxybiphen-4-yl)methyl-4-methylamino-6-trifluoromethyl-8-ethylpurine;

(153)9-(2'-Carboxybiphen-4-yl)methyl-4,6-dimethyl-8-(2,2,2-trifluoro)ethylpurine;

(154)9-(2'-Carboxybiphen-4-yl)methyl-4,6-dimethyl-8-(3,3,3-trifluoro)propylpurine;

(155)9-(2'-Carboxybiphen-4-yl)methyl-4,6-dimethyl-8-(2,2-difluoro)propylpurine;

(156) 8-Butyl-9-(2'-carboxybiphen-4-yl)methyl-6-chloropurine;

(157) 8-Butyl-9-(2'-carboxybiphen-4-yl)methyl-6-hydroxypurine;

(158) 4-Carboxy-9-(2'-carboxybiphen-4-yl)methyl-6-methyl-8-ethylpurine;

(159)4-Carbomethoxy-9-(2'-carboxybiphen-4-yl)methyl-6-methyl-8-ethylpurine;

(160)9-(2'-Carboxybiphen-4-yl)methyl-8-ethyl-4-hydroxymethyl-6-methylpurine;

(161) 6-Chloro-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(162) 6-Methyl-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(163) 8-Ethyl-6-methyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(164)4,6-Dimethyl-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(165)4,6-Dimethyl-8-ethyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(166)6-Methyl-2-methylamino-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(167)4-Dimethylamino-8-ethyl-6-methyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(168)8-Ethyl-6-methyl-4-methylamino-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(169)8-Ethyl-6-methyl-4-(morpholin-4-yl)-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(170) 8-Propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(171) 8-Butyl-6-chloro-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(172) 8-Butyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(173)2-Chloro-6-methyl-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(174)6-Methyl-2-(morpholin-4-yl)-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(175)8-Ethyl-4-ethylamino-6-methyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(176)8-Ethyl-6-methyl-4-propylamino-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(177)8-Ethyl-4-methylamino-6-trifluoromethyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(178)4,6-Dimethyl-8-(2,2,2-trifluoro)ethyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(179)4,6-Dimethyl-8-(3,3,3-trifluoro)propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(180)8-(2,2-Difluoro)propyl-4,6-dimethyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(181)4-Carboxy-8-ethyl-6-methyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(182)4-Carbomethoxy-8-ethyl-6-methyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine;

(183)8-Ethyl-4-hydroxymethyl-6-methyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurineand;

(184)8-Butyl-1,3-dimethyl-7-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-1,2,3,6-tetrahydro-2,6-dioxopurine.

The compounds of Formula (I) can be synthesized using the reactions andtechniques described herein below. The reactions are performed in asolvent appropriate to the reagents and materials employed and suitablefor the transformation being effected. It is understood by those skilledin the art of organic synthesis that the functionality present on theheterocycle and in the reactants being employed should be consistentwith the chemical transformations being conducted. Depending upon thereactions and techniques employed, optimal yields may require changingthe order of synthetic steps or use of protecting groups followed bydeprotection.

    ______________________________________                                        ABBREVIATIONS USED IN REACTION SCHEMES                                        ______________________________________                                        Reagents:                                                                     NBS             N-bromosuccinimide                                            AIBN            Azo(bis)isobutyronitrile                                      DDQ             Dichlorodicyanoquinone                                        Ac.sub.2 O      acetic anhydride                                              TEA             triethylamine                                                 DMAP            4-dimethylaminopyridine                                       PPh.sub.3       triphenylphosphine                                            TFA             trifluoroacetic acid                                          TMS-Cl          trimethylsilyl chloride                                       Im              imidazole                                                     AcSK            potassium thioacetate                                         p-TsOH          p-toluenesulfonic acid                                        Solvents:                                                                     Et.sub.2 O      diethyl ether                                                 DMF             dimethylformamide                                             HOAc (AcOH)     acetic acid                                                   EtOAc (EtAc)    ethyl acetate                                                 Hex             hexane                                                        THF             tetrahydrofuran                                               DMSO            dimethylsulfoxide                                             MeOH            methanol                                                      iPrOH           isopropanol                                                   DBU             1,8-diazabicyclo-[5.4.0]                                                      undec-7-ene                                                   Me.sub.3 SnCl   trimethylstannyl chloride                                     Others:                                                                       rt              room temperature                                              TBDMS           t-butyldimethylsilyl                                          OTf             OSO.sub.2 CF.sub.3                                            OTs             OSO.sub.2 -(4-methyl)phenyl                                   OMs             OSO.sub.2 CH.sub.3                                            Ph              phenyl                                                        FAB-MS (FABMS)  Fast atom bombardment mass                                    spectroscopy                                                                  NOE             Nuclear Overhauser Effect                                     SiO.sub.2       silica gel                                                    trityl          triphenylmethyl                                               ______________________________________                                    

As shown in Reaction Scheme 1, compounds of Formula I can be prepared bycarrying out direct alkylation of alkali-metal salts of heterocycles (1)(preparation of heterocycles are described in Reaction Schemes 3-6)using appropriately protected benzyl halide, tosylate (OTs) or mesylate(OMs) derivatives (2). The salt is prepared preferably using MH (where Mis lithium, sodium or potassium) in anhydrous dimethylformamide (DMF),or by treating it with a metal alkoxide such as sodium or potassiummethoxide, ethoxide or t-butoxide in an appropriate alcohol such asmethanol, ethanol or t-butanol as the solvent. The alkylation isgenerally carried out by dissolving the metal salt of the heterocycle ina dipolar aprotic solvent such as DMF or dimethylsulfoxide (DMSO) andreacting it with the alkylating agent at 20° C. to reflux temperature ofthe solvent for 1-24 hours. ##STR42##

If substituents and/or the hetero atom positions in the six-memberedring are not symetrically disposed, the alkylation on the imidazolenitrogen(s) generally produces a mixture of two regioisomers as productsarising from N¹ and N³ alkylation. These regioisomers I and Ia possessdistinct physico-chemical and biological properties and in most casescan be separated and purified by using conventional separationtechniques such as chromatography (flash column chromatography,medium-pressure liquid chromatography, high performance liquidchromatography) and/or crystallization. In those cases where separationof regioisomers is difficult by conventional techniques, the mixture canbe transformed into suitable derivatives that can be separated by theabove separation methods. The structural assignments of the isomers canbe made using Nuclear Overhauser Effect (NOE), ¹ H-¹³ C coupled NMRexperiments or X-ray crystallography.

When there is potential for alkylation in the 6-membered heterocyclicring, this can be avoided by the use of suitable protecting groups.

The substituted benzyl halides (2) including the more preferredalkylating agents (8a and 8b and 8c, Reaction Scheme 2) can be preparedas described in European Patent Applications 253,310 and 291,969 and thereferences cited therein. In addition a preferred method to prepare thebiphenyl precursors 7a, 7b using Ni(0) or Pd(O) catalyzed cross-couplingreaction [E. Negishi, T. Takahashi, and A. O. King, Org. Synthesis, 66,67 (1987)] is outlined in Reaction Scheme 2. As shown in Reaction Scheme2, treatment of 4-bromotoluene (3) with t-BuLi, followed by the additionof a solution of ZnCl₂, produces the organo-zinc compound (5). Compound(5) is then coupled with 6a or 6b in the presence of Ni(PPh₃)Cl₂catalyst to produce the desired biphenyl compound 7a or 7b. Similarly,1-bromo-2-nitrobenzene (6c) is coupled with organo-zinc compound 5 inthe presence of Pd(PPh₃)₄ catalyst [prepared by treating Cl₂ Pd(PPh₃)₂with (i-Bu)₂ AlH (2 equiv.)] to give the biphenyl compound 7c. Theseprecursors, 7a, 7b and 7c, are then transformed into halomethylbiphenylderivatives 8a, 8b and 8c, respectively, according to proceduresdescribed in European Patent Applications 253,310 and 291,969.

When there is additional substitution on the second phenyl ring (R² nothydrogen) the preferred method to prepare the biphenyl precursors 7d and7e, using the Pd(0) catalyzed cross-coupling reaction [J. K. Stille,Angrew, Chem. Int. Ed. Engl., 25, 508 (1986)], is outlined in reactionScheme 2a. As shown in reaction Scheme 2a, p-tolytrimethyltin (5a) iscoupled with 6d or 6e in refluxing toluene in the presence of 5 mole %of Pd(PPh₃)₄ to produce the desired biphenyl compounds 7d and 7e. TableI illustrates the synthetic utility of this protocol. Compounds 7d (R²=NO₂) and 7e (R² =NO₂) could be converted to their respective chloridesby catalytic hydrogenation, diazotization and treatment with copper (I)chloride. The biphenyl fluorides which could not be obtained by directcoupling to a fluoro arylbromide were prepared from 7d (R² =NO₂) and 7e(R² =NO₂) via reduction, formation of the diazonium tetrafluoroboratesalt and thermal decomposition. These precursors 7d (R² =NO₂ or F or Cl)and 7e (R² =NO₂ or F or Cl) are then transformed into the halomethylbiphenyl derivatives 8d and 8e, respectively according to the proceduresdescribed in European Patent Applications 253,310 and 292,969. ##STR43##

    __________________________________________________________________________    Biphenyl Synthesis Table I                                                    X R.sup.1                                                                            R.sup.a                                                                          R.sup.b                                                                          R.sup.c                                                                          R.sup.d                                                                          Product (R.sup.a)                                                                    Rf (solvent) Yield                                  __________________________________________________________________________    Br                                                                              CO.sub.2 Me                                                                        NO.sub.2                                                                         H  H  H  7d (3'-nitro)                                                                        0.35(15:1 Hex/EtOAc)                                                                       71%                                    Br                                                                              CN   H  NO.sub.2                                                                         H  H  7e (4'-nitro)                                                                        0.62(2x 6:1 Hex/EtOAc)                                                                     74%                                    Br                                                                              CO.sub.2 Me                                                                        H  F  H  H  7d (4'-fluoro)                                                                       0.43(15:1 Hex/EtOAc)                                                                       83%                                    Cl                                                                              CO.sub.2 Me                                                                        H  H  NO.sub.2                                                                         H  7d (5'-nitro)                                                                        0.22(15:1 Hex/EtOAc)                                                                       70%                                    Br                                                                              CO.sub.2 Me                                                                        H  H  H  NO.sub.2                                                                         7d (6'-nitro)                                                                        0.24(15:1 Hex/EtOAc)                                                                       79%                                    Br                                                                              CN   H  F  H  H  7e (4'-fluoro)                                                                       0.44(15:1 Hex/EtOAc)                                                                       64%                                    Cl                                                                              CN   H  H  F  H  7e (5'-fluoro)                                                                       0.40(15:1 Hex/EtOAc)                                                                       62%                                    __________________________________________________________________________

The heterocycles of type (1) can be prepared by any of the standardprocedures described in the literature [J. A. Montgomery and J. A.Secrist III in "Comprehensive Heterocyclic Chemistry," Vol. 5, A. R.Katritsky and C. W. Rees Eds., Pergamon Press 1984; pp 567-597 and631-656 and references cited therein]. As shown in Reaction Scheme 3,the most widely used starting materials are six member heterocyclicvicinal diamines (9). Fused imidazoles (10) can be prepared bycondensation of (9) with an appropriate carboxylic acid, nitrile,imidate ester, or orthoesters, either neat, or in a solvent appropriateand compatible with the starting materials and reagents, such aspolyphosphoric acid, ethanol, methanol, hydrocarbon solvents, and with acatalytic amount of acid if required. Oxidation of an imine formed byreaction of diamine (9) with an appropriate aldehyde using oxidants suchas Cu (II), nitrobenzene, or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ) also affords heterocycles (10). Aminoamides (11, W=H) or diamides(11, W=R⁶ CO) can be converted to fused imidazoles (10) by heating neat,or at an elevated temperature in a solvent such as xylene under acidicor neutral conditions.

As shown in Reaction Scheme 4, methods of preparing heterocycles oftypes (12 and 13) involve treatment of diamines (9) with reagents suchas urea, phosgene, potassium cyanate, alkyl chloroformates,dialkylcarbonate, or carbon disulfide in the presence of bases such aspotassium hydroxide or potassium carbonate. Amino acids (14) of (15) canbe converted to (13) via Curtius or Hoffman rearrangement on suitablederivatives such as acyl azides, hydroxyamides, or N-haloamides.Bicyclic compounds of type (16, E=sulfur or oxygen) are formed from 12by reaction under neutral or basic conditions with alkyl halides,alkylmesylates, alkyltosylates, trialkyloxonium salts, or with anappropriate diazoalkane. Compounds of type (16; E=oxygen or sulfur) areprepared by displacement reactions using alkoxides or alkyl mecaptideswith chloro intermediates as indicated.

Diamines of type 9 can be prepared by a wide variety of methods such ashydrolysis of bis-amides or amino amides, reduction of dinitro oraminonitro or hydrazino or azido groups, displacement of heteroaromatichalides or alkoxy or thio or alkylthio or hydroxy or alkyl sulfonylgroups with ammonia or amines, or rearrangement of acyl azides or amidesor acids (Curtius, Hofman, or Schmidt rearrangements). [A. S. Tomcufcik,L. N. Starker in "Heterocyclic Compounds, Pyridine and it's Derivatives"Pt 3, E. Klingsberg Ed., Wiley Interscience, 1962, pp 59-62, andreferences cited there in; T. Nakagome in "Heterocyclic Compounds,Pyridazines" Vol. 28, R. N. Castle, Ed., Wiley Interscience, 1973, pp597-601, and references cited therein; "Heterocyclic Compounds, ThePyrimidines" Vol. 16, D. J. Brown Ed., Wiley Interscience 1985, pp299-325; E. Schipper, and A. R. Day J. Am. Chem. Soc. (1952) 74, 350;"Comprehensive Heterocyclic Chemistry," Vol. 5, A. R. Katritsky and C.W. Rees Eds., Pergamon Press 1984; pp 567-597 and 631-656 and referencescited therein].

In cases wherein heterocycles of type 10 or 16 are not easily preparedfrom their corresponding diamines, or when these diamines cannot beprepared then alternative routes, involving fusion of the six memberheterocycle onto an appropriately substituted imidazole, are used. Twoof these routes are illustrated in Reaction Scheme 5. For example,imidazo[4,5-d][1,2,3]triazines (18) are preferentially prepared bytreatment of amino carboxamido imidazoles (17) with sodium nitrite inaqueous acid. Precursor imidazoles (17) are prepared by degradation ofan appropriately substituted xanthine or by condensation of anappropriate imidate ester with aminocyanoacetamide.Imidazo[4,5-b]pyridazines (20) can be prepared from imidazodicarboxylateesters (19) by treatment with hydrazine. Oxidation of (20) givespyridazindiones (21). The oxygen(s) in (20) or (21) can be converted toother functionalities such as halides or thiones, which are themselvesprecursors for the synthesis of more elaborate systems ["ComprehensiveHeterocyclic Chemistry," Vol. 5, A. R. Katritsky and C. W. Rees Eds.,Pergamon Press 1984 ; pp 567-597 and 631-656 and references citedtherein]. ##STR44##

Moreover, as shown in Reaction Scheme 6, amino imidazole esters andamides are versatile intermediates for the preparation of purines. Thisscheme also illustrates the synthesis of the 6-membered heterocyclicring after the alkylating agent 2 has been reacted with a suitablysubstituted imidazole to afford 22 or 24. ##STR45##

The preparation of reduced forms of heterocycles can be achieved bycatalytic reduction, or by synthesis from a suitable imidazoleprecursor. For example, histidine and derivatives thereof react withformaldehyde to afford partially saturated imidazo(4,5-c) pyridines [cf.Neuberger, A. Biochem. J., (1944), 38, 309].

Compounds of formula I where R¹ is --CONHSO₂ R²³ (where R²³ =alkyl, arylor heteroaryl) may be prepared from the corresponding carboxylic acidderivatives (I) as outlined in Scheme 7. The carboxylic acid (I),obtained as described in Scheme 1, can be converted into thecorresponding acid chloride by treatment with refluxing thionyl chlorideor preferably with oxalylchloride and a catalytic amount ofdimethylformamide at low temperature [A. W. Burgstahler, L. O. Weigel,and C. G. Shaefer--Synthesis, 767, (1976)]. The acid chloride then canbe treated with the alkali metal salt of R²³ SO₂ NH₂ to form the desiredacylsulfonamide 26. Alternatively, these acylsulfonamides may be alsoprepared from the carboxylic acids using N,N-diphenylcarbamoyl anhydrideintermediates [F. J. Brown et al--European Patent Application, EP199543; K. L. Shepard and W. Halczenko--J. Het. Chem., 16, 321 (1979)].Preferably the carboxylic acids can be converted into acyl-imidazoleintermediates, which then can be treated with an appropriate aryl oralkylsulfonamide and diazabicycloundecane (DBU) to give the desiredacylsulfonamide 26 [J. T. Drummond and G. Johnson--Tetra. Lett., 29,1653 (1988)]. ##STR46##

Compounds of formula I where R¹ is --SO₂ NHCOR²³ may be prepared asoutlined in Scheme 8. The nitro compound 7c (prepared as described inScheme 2) can be reduced to the corresponding amino compound andconverted into aromatic diazonium chloride salt, which then can bereacted with sulfur-dioxide in the presence of a copper(II) salt to formthe corresponding arylsulfonylchloride 27 [H. Meerwein, G. Dittmar, R.Gollner, K. Hafner, F. Mensch and O. Steifort--Chem. Ber., 90, 841(1957); A. J. Prinsen and H. Cerfontain, Recueil, 84, 24 (1965); E. E.Gilbert, Synthesis, 3 (1969) and references cited therein]. The sulfonylchloride can be reacted with ammonia in aqueous solution or in an inertorganic solvent [F. H. Bergheim and W. Baker, J. Amer. Chem. Soc., 66,(1944), 1459], or with dry powdered ammonium carbonate, [E. H. Huntressand J. S. Autenrieth, J. Amer. Chem. Soc., 63, (1941), 3446; E. H.Huntress and F. H. Carten, J. Amer. Chem. Soc., 62, (1940), 511] to formthe sulfonamide 28. The benzylbromide 30 may be prepared from thesulfonamide 28 as outlined in Scheme 8, and then can be reacted with analkali metal salt of an appropriate heterocyclic compound to form thekey sulfonamide 31. The sulfonamide 31 may be also prepared from thearomatic sulfonyl chloride 36, which may be prepared from the aryl amine35 as outlined in Scheme 9. The acylation of 31 with appropriate acylchlorides (or acyl-imidazoles or other acylating agents) may produce thedesired acylsulfonamides 32. ##STR47##

The compounds bearing R¹ as --SO₂ NHR²³ (where R²³ is heteroaryl) may beprepared by reacting the aromatic sulfonyl chloride 36 with appropriateheteroaryl amines as outlined in Scheme 9. The sulfonyl chloride 36 maybe the prefered intermediate for the synthesis of this class ofcompounds. The aromatic sulfonyl chlorides may also be prepared byreacting the sodium salt of aromatic sulfonic acids with PCl₅ or POCl₃[C. M. Suter, The organic Chemistry of Sulfur, John Wiley & sons, 459,(1944)]. The aromatic sulfonic acid precursors may be prepared bychlorosulfonation of the aromatic ring with chlorosulfonic acid [E. H.Huntress and F. H. Carten, J. Amer. Chem. Soc., 62, 511 (1940)].##STR48##

The biaryl sulfonamides 28a and 29 can be prepared alternatively usingpalladium(0) catalyzed cross-coupling reactions of appropriatearyl-organotin precursors [J. K. Stille, Pure Appl. Chem., 57, 1771(1985); T. R. Baiely, Tetra Lett., 27, 4407 (1986); D. A. Widdowson andY. Z. Zhang, Tetrahedron, 42, 2111 (1986)], as outlined in Scheme 10.The organotin compound 39 [S. M. Moerlein, J. Organometallic Chem., 319,29 (1987)], obtained from the aromatic precursor 38, may be coupled witharyl sulfonamides 41 and 42 using Pd(PPh₃)₄ or (PPh₃)₂ PdCl₂ ascatalysts to give biaryl sulfonamides 28a and 29, respectively.Similarly, the benzyl bromide 30 may be alternatively prepared from theappropriate organotin precursor 45 using the Pd(0) catalyzedcross-coupling reaction as outlined in Scheme 11.

The compounds bearing R¹ as --CH₂ SO₂ NHCOR²³ and --CH₂ SO₂ NHR²³ may beprepared as outlined in Scheme 12. The key precursoraryl-methanesulfonyl chloride 52 may be prepared either from thereaction of aryl-methylmagnesium chloride (51) (obtained from thecorresponding benzyl chloride (48)) with sulfurylchloride [S. N.Bhattacharya, C. Eaborn and D. P. M. Walton, J. Chem. Soc. C, 1265(1968)], or by oxidation of the aryl-methylthioacetate (50) (preparedfrom the benzyl bromide 49) with chlorine in presence of trace amount ofwater [Bagnay and Dransch, Chem. Ber., 93, 784 (1960)]. Alternatively,the aryl-methylthioacetate (50) may be oxidized with sulfuryl chloridein presence of acetic anhydride to form aryl-methylsulfinyl chloride [S.Thea and G. Cevasco, Tetra. Lett., 28, 5193 (1987)], which can befurther oxidized with appropriate oxidizing agents to give the sulfonylchloride 52. The compounds 53 and 54 can be obtained by reacting thesulfonyl chloride 52 with appropriate amines.

Compounds where R¹ =--NHSO₂ NHR²³ may be prepared by the reaction ofappropriate primary amines with the sulfamide 56 [S. D. McDermott and W.J. Spillane, Synthesis, 192 (1983)], as described in Scheme 13. Thecompound 56 may be obtained from the corresponding N-t-butylsulfamide 55after treatment with anhydrous trifluoroacetic acid [J. D. Catt and W.L. Matier, J. Org. Chem., 39, 566 (1974)], which may be prepared by thereaction of the aromatic amine 35 with t-butylsulfamoyl chloride [W. L.Matier, W. T. Comer and D. Deitchman, J. Med. Chem., 15, 538 (1972)].

Antagonists of Formula I in which R¹ =--NHSO₂ CF₃ may be prepared asillustrated in Schemes 9 and 14. Bromination of 7c (prepared asdescribed in Scheme 2) with N-bromosuccinimide affords4-bromomethyl-2'-nitrobiphenyl (33). This bromide is then used toalkylate the sodium salt of an appropriate heterocyclic compound inanhydrous DMF, affording 34. Subjection of 34 to catalytic reductionwith Pd/C catalyst then affords the corresponding amino-derivative 35,which is converted upon treatment with trifluoromethansulfonic anhydrideto the sulfonamide 58.

Antagonists of Formula I in which R¹ =--CH₂ SO₂ NHCOR²³ may be preparedas illustrated in Scheme 15. 2-Bromotoluene (59) is treated witht-butyllithium and then zinc chloride. Coupling of the resultingmetallo-zinc species with 4-bromobenzoic acid methyl ester (60) is thencarried out with bis(triphenylphosphine)nickle(II) chloride as catalyst.Bromination of the resulting biphenyl (61) is then carried out usingN-bromosuccinimide, affording bromide 62. Treatment of the bromide withthiourea affords the salt 63 which is treated with chlorine to yieldsulfonyl chloride 64. Treatment of 64 with t-butylamine affordssulfonamide 65, which is converted by treatment with lithium aluminumhydride to the alcohol 66. Conversion of 66 to the corresponding iodide67 is carried out by treatment with methanesulfonyl chloride to afford asulfonate ester, followed by treatment with sodium iodide in acetone.The iodide 67 is used to alkylate the sodium salt of an appropriateheterocyclic compound, affording the sulfonamide 68. Treatment of 68with trifluoroacetic acid then affords the sulfonamide analog 69, whichon further treatment with acetic anhydride and pyridine affords thedesired acylsulfonamides 70.

Halogenation of the imidazo[4,5-b]pyridine ring at the 6-position can beaccomplished using Br₂, or N-bromosuccinimide. Halogenation of the7-position can be accomplished by reaction of the correspondingimidazopyridine-4-oxide (prepared by reaction of the imidazopyridinewith peracids such as m-chloroperbenzoic acid) with POCl₃. When the7-position is substituted with other than hydrogen, halogenation at the5-position of the 4(N)-oxide precursor occurs upon treatment with POCl₃.Chlorides may be substistuted by bromides or iodides by treatment witheither HBr or HI, respectively, in a solvent such as HOAc.

2-Alkyl-imidazo[4,5-b]pyridines can be substituted at the 5, 6, or 7positions by displacement of a halogen at that position by nucleophilessuch as cyanide, amines, copper alkoxides, trialkylphosphites, andthiolates. Also, substitution of the halogens, in particular bromides oriodides, can be accomplished by reaction with a coupling partner such asalkylzinc or arylzinc halides, or monoalkylarylphosphonites in thepresence of an appropriate metal catalyst such as nickle, palladium,ruthenium, or platinum. In cases where the reaction is sluggish orcomplicated due to an acidic proton, the imidazopyridine may beprotected at the 1, 3, or 4 positions by benzyl or other arylmethylgroups.

It will be appreciated by those skilled in the art that functional grouptransformations can be conducted on aryl and heterocyclic rings toafford desired analogs. For example, esters may be converted to amidesby heating them with amines and an amide nitrogen if present in theheterocycle may be alkylated using bases such as sodium hydride in DMFwith the appropriate alkyl halide. Functional group protectionthroughout these syntheses will be chosen to be compatible withsubsequent reaction conditions. Ultimately such protecting groups willbe removed to generate the desired optimally active compounds of FormulaI. For example, R¹ as carboxyl is often protected as its t-butyl esterwhich in the last step is removed by treatment with trifluoroaceticacid. Aqueous acetic acid at room temperature overnight is a preferredmethod to remove a trityl protecting group to liberate an R¹ tetrazolegroup.

The compounds of this invention form salts with various inorganic andorganic acids and bases which are also within the scope of theinvention. Such salts include ammonium salts, alkali metal salts likesodium and potassium salts, alkaline earth metal salts like the calciumand magnesium salts, salts with organic bases; e.g., dicyclohexylaminesalts, N-methyl-D-glucamine, salts with amino acids like arginine,lysine, and the like. Also, salts with organic and inorganic acids maybe prepared; e.g., HCl, HBr, H₂ SO₄, H₃ PO₄, methane-sulfonic,toluene-sulfonic, maleic, fumaric, camphorsulfonic. The non-toxic,physiologically, acceptable salts are preferred, although other saltsare also useful; e.g., in isolating or purifying the product.

The salts can be formed by conventional means such as by reacting thefree acid or free base forms of the product with one or more equivalentsof the appropriate base or acid in a solvent or medium in which the saltis insoluble, or in a solvent such as water which is then removed invacuo or by freeze-drying or by exchanging the cations of an existingsalt for another cation on a suitable ion exchange resin.

Angiotensin II (AII) is a powerful arterial vasoconstrictor, and itexerts its action by interacting with specific receptors present on cellmembranes. The compounds described in the present invention act ascompetitive antagonists of AII at the receptors. In order to identifyAII antagonists and determine their efficacy in vitro, the following twoligand-receptor binding assays were established.

RECEPTOR BINDING ASSAY USING RABBIT AORTAE MEMBRANE PREPARATION

Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) weresuspended in 5 mM Tris-0.25M Sucrose, pH 7.4 buffer (50 ml) homogenized,and then centrifuged. The mixture was filtered through a cheesecloth andthe supernatant was centrifuged for 30 minutes at 20,000 rpm at 4° C.The pellet thus obtained was resuspended in 30 ml of 50 mM Tris-5 mMMgCl₂ buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/mlBacitration and the suspension was used for 100 assay tubes. Samplestested for screening were done in duplicate. To the membrane preparation(0.25 ml) there was added ¹²⁵ I-Sar¹ Ile⁸ -angiotensin II [obtained fromNew England Nuclear] (10 ul; 20,000 cpm) with or without the test sampleand the mixture was incubated at 37° C. for 90 minutes. The mixture wasthen diluted with ice-cold 50 mM Tris-0.9% NaCl, pH 7.4 (4 ml) andfiltered through a glass fiber filter (GF/B Whatman 2.4" diameter). Thefilter was soaked in scintillation cocktail (10 ml) and counted forradioactivity using Packard 2660 Tricarb liquid scintillation counter.The inhibitory concentration (IC₅₀) of potential AII antagonist whichgives 50% displacement of the total specifically bound ¹²⁵ I-Sar¹ Ile⁸-angiotensin II was presented as a measure of the efficacy of suchcompounds as AII antagonists.

RECEPTOR ASSAY USING BOVINE ADRENAL CORTEX PREPARATION

Bovine adrenal cortex was selected as the source of AII receptor.Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended inTris.HCl (50 mM), pH 7.7 buffer and homogenized. The homogenate wascentrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded andpellets resuspended in buffer [Na₂ HPO₄ (10 mM)-NaCl (120 mM)-disodiumEDTA (5 mM) containing phenylmethane sulfonyl fluoride (PMSF) (0.1 mM)].(For screening of compounds, generally duplicates of tubes are used). Tothe membrane preparation (0.5 ml) there was added 3H-angiotensin II (50mM) (10 ul) with or without the test sample and the mixture wasincubated at 37° C. for 1 hour. The mixture was then diluted with Trisbuffer (4 ml) and filtered through a glass fiber filter (GF/B Whatman2.4" diameter). The filter was soaked in scintillation cocktail (10 ml)and counted for radioactivity using Packard 2660 Tricarb liquidscintillation counter. The inhibitory concentration (IC₅₀) of potentialAII antagonist which gives 50% displacement of the total specificallybound ³ H-angiotensin II was presented as a measure of the efficacy ofsuch compounds as AII antagonists.

The antihypertensive effects of the compounds described in the presentinvention may be evaluated using the methodology described below:

Male Charles River Sprague-Dawley rats (300-375 gm) were anesthetizedwith methohexital (Brevital; 50 mg/kg i.p.) and the trachea wascannulated with PE 205 tubing. A stainless steel pithing rod (1.5 mmthick, 150 mm long) was inserted into the orbit of the right eye anddown th spinal column. The rats were immediately placed on a HarvardRodent Ventilator (rate--60 strokes per minute, volunm--1.1 cc per 100grams body weight). The right carotid artery was ligated, both left andright vagal nerves were cut, and the left carotid artery was cannulatedwith PE 50 tubing for drug administration, and body temperature wasmaintained at 37° C. by a thermostatically controlled heating pad whichreceived input from a rectal temperature probe. Atropine (1 mg/kg i.v.)was then administered, and 15 minutes later propranolol (1 mg/kg i.v.).Thirty minutes later angiotensin II or other agonists were administeredintravenously at 30-minute intervals and the increase in the diastolicblood pressure was recorded before and after drug or vehicleadministration.

Using the methodology described above, representative compounds of thisinvention were evaluated and were found to exhibit an activity of atleast IC₅₀ <50 μM, thereby demonstrating and confirming the utility ofthe compounds of the invention as effective A II antagonists.

The compounds of the invention are useful in treating hypertension. Theyare also of value in the management of acute and chronic congestiveheart failure. These compounds may also be expected to be useful in thetreatment of secondary hyperaldosteronism, primary and secondarypulmonary hyperaldosteronism, primary and secondary pulmonaryhypertension, renal failure such as diabetic nephropathy,glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria ofprimary renal disease, end stage renal disease, renal transplanttherapy, and the like, renal vascular hypertension, left ventriculardysfunction, diabetic retinopathy and in the management of vasculardisorders such as migraine, Raynaud's disease, luminal hyperclasia, andto minimize the atherosclerotic process. The application of thecompounds of this invention for these and similar disorders will beapparent to those skilled in the art.

The compounds of this invention are also useful to treat elevatedintraocular pressure and to enhance retinal blood flow and can beadministered to patients in need of such treatment with typicalpharmaceutical formulations such as tablets, capsules, injectables andthe like as well as topical ocular formulations in the form ofsolutions, ointments, inserts, gels, and the like. Pharmaceuticalformulations prepared to treat intraocular pressure would typicallycontain about 0.1% to 15% by weight, preferably 0.5% to 2% by weight, ofa compound of this invention.

In the management of hypertension and the clinical conditions notedabove, the compounds of this invention may be utilized in compositionssuch as tablets, capsules or elixirs for oral administration,suppositories for rectal administration, sterile solutions orsuspensions for parenteral or intramuscular administration, and thelike. The compounds of this invention can be administered to patients(animals and human) in need of such treatment in dosages that willprovide optimal pharmaceutical efficacy. Although the dose will varyfrom patient to patient depending upon the nature and severity ofdisease, the patient's weight, special diets then being followed by awhich those skilled in the art will recognize, the dosage range willgenerally be about 1 to 1000 mg. per patient per day which can beadministered in single or multiple doses. Perferably, the dosage rangewill be about 2.5 to 250 mg. per patient per day; more preferably about5 to 150 mg. per patient per day.

The compounds of this invention can also be administered in combinationwith other antihypertensives and/or diuretics and/or angiotensinconverting enzyme inhibitors and/or calcium channel blockers. Forexample, the compounds of this invention can be given in combinationwith such compounds as amiloride, atenolol, bendroflumethiazide,chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates andcryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate,hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprololtartate, methyclothiazide, methyldopa, methyldopate hydrochloride,minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol,rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside,spironolactone, timolol maleate, trichlormethiazide, trimethophancamsylate, benzthiazide, quinethazone, ticrynafan, triamterene,acetazolamide, aminophylline, cyclothiazide, ethacrynic acid,furosemide, merethoxylline procaine, sodium ethacrynate, captopril,delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium,lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide,zofenopril calcium, diflusinal, diltiazem, felodipine, nicardipine,nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, and thelike, as well as admixtures and combinations thereof.

Typically, the individual daily dosages for these combinations can rangefrom about one-fifth of the minimally recommended clinical dosages tothe maximum recommended levels for the entities when they are givensingly.

To illustrate these combinations, one of the angiotensin II antagonistsof this invention effective clinically in the 2.5-250 milligrams per dayrange can be effectively combined at levels at the 0.5-250 milligramsper day range with the following compounds at the indicated per day doserange: hydrochlorothiazide (15-200 mg) chlorothiazide (125-2000 mg),ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg),propranolol (20-480 mg), timolol maleate (5-60 mg.), methyldopa (65-2000mg), felodipine (5-60 mg), nifedipine (5-60 mg), and nitrendipine (5-60mg). In addition, triple drug combinations of hydrochlorothiazide(15-200 mg) plus amiloride (5-20 mg) plus angiotensin II antagonist ofthis invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plustimolol maleate (5-60) plus an angiotensin II antagonist of thisinvention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine(5-60 mg) plus an angiotensin II antagonist of this invention (0.5-250mg) are effective combinations to control blood pressure in hypertensivepatients. Naturally, these dose ranges can be adjusted on a unit basisas necessary to permit divided daily dosage and, as noted above, thedose will vary depending on the nature and severity of the disease,weight of patient, special diets and other factors.

Typically, these combinations can be formulated into pharmaceuticalcompositions as discussed below.

About 1 to 100 mg. of compound or mixture of compounds of Formula I or aphysiologically acceptable salt is compounded with a physiologicallyacceptable vehicle, carrier, excipient, binder, preservative,stabilizer, flavor, etc., in a unit dosage form as called for byaccepted pharmaceutical practice. The amount of active substance inthese compositions or preparations is such that a suitable dosage in therange indicated is obtained.

Illustrative of the adjuvants which can be incorporated in tablets,capsules and the like are the following: a binder such as gumtragacanth, acacia, corn starch or gelatin; an excipient such asmicrocrystalline cellulose; a disintegrating agent such as corn starch,pregelatinized starch, alginic acid and the like; a lubricant such asmagnesium stearate; a sweetening agent such as sucrose, lactose orsaccharin; a flavoring agent such as peppermint, oil of wintergreen orcherry. When the unit dosage unitform is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier such as fattyoil. Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit. For instance, tablets maybe coated with shellac, sugar or both. A syrup or elixir may contain theactive compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Sterile compositions for injection can be formulated according toconventional pharmaceutical practice by dissolving or suspending theactive substance in a vehicle such as water for injection, a naturallyoccuring vegetable oil like sesame oil, coconut oil, peanut oil,cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate orthe like. Buffers, preservatives, antioxidants and the like can beincorporated as required.

The following examples further illustrate the preparation of thecompounds of Formula I and their incorporation into pharmaceuticalcompositions and, as such, are not to be considered or construed aslimiting the invention recited in the appended claims.

EXAMPLE 1 Preparation of 2-t-Butoxycarbonyl-4'-bromomethylbiphenyl

Step 1: 2-t-Butoxycarbonyl-4'-methylbiphenyl

To a solution of p-bromotoluene (30 g) in dry ether (150 ml) at -78° C.,a solution of t-BuLi in pentane (1.7M) (210 ml) was added slowly over aperiod of 1 hour and 30 minutes, using a dropping funnel. The bath wasthen removed and the mixture was stirred at room temperature for anadditional 2 hours. The content of the flask was then added slowly(using a cannula) at room temperature to a premixed solution of ZnCl₂ inether (1M) (180 ml) and dry THF (360 ml). The mixture was stirred for 2hours at that temperature and the slurry was added (using a cannula) toa solution of 2-t-butoxycarbonyliodobenzene (35.6 g), and NiCl₂ (Ph₃ P)₂(2.1 g) in dry THF (360 ml). The mixture, after stirring at roomtemperature overnight (18 hours), was poured slowly under stirring intoice-cold 0.5N HCl (1500 ml). The organic layer was separated, and theaqueous phase was extracted with ether (3×300 ml). The combined organiclayer was washed with water, brine and then dried over MgSO₄. Removal ofthe solvent gave the crude product as an oil (32 g). The material waspurified on a silica gel flash column using ethylacetate/hexane (1:12)to give the titled compound as an oil (24 g, 76%).

NMR (CDCl₃) δ1.24 (s, 9H), 2.42 (s, 3H), 7.2-7.8 (m, 8H); FAB-MS: m/e269 (M+H).

Step 2: 2-t-Butoxycarbonyl-4'-bromomethylbiphenyl

The titled compound was prepared from2-t-Butoxycarbonyl-4'-methylbiphenyl (obtained from Step 1) according tothe procedure described in European Patent Application EP 0,253,310.

EXAMPLE 2 Preparation ofN-Triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole

Step 1: 2-cyano-4'-methylbiphenyl

To a solution of p-bromotoluene (30 g) in dry ether (150 ml) at -78° C.,a solution of t-BuLi in pentane (1.7M) (210 ml) was added slowly over aperiod of 1 hour and 30 minutes, using a dropping funnel. The bath wasthen removed and the mixture was stirred at room temperature for anadditional 2 hours. The content of the flask was then added slowly(using a cannula) at room temperature to a premixed solution of ZnCl₂ inether (1M) (180 mL) and dry THF (360 mL). The mixture was stirred for 2hours at that temperature and the slurry was added (using a cannula) toa solution of 2-bromobenzonitrile (21.3 g) and NiCl₂ (Ph₃ P)₂ (2.1 g) indry THF (300 ml). The mixture, after stirring at room temperatureovernight (18 hours), was poured slowly under stirring into ice cold0.5N HCl (1500 ml). The organic layer was separated, and the aqueousphase was extracted with ether (3×300 ml). The combined organic layerwas washed with water, brine and then dried over MgSO₄. Removal of thesolvent gave the crude product as a semisolid mass (34 g). The materialwas purified on a silica gel flash column using ethylacetate/hexane(1:12) to give the desired nitrile as a low melting solid (28 g, 88 %).

NMR (CDCl₃) δ2.42 (s, 3H), 7.2-7.8 (m, 8H).

FAB-MS: m/e 194 (M+H).

Step 2: Trimethylstannyl azide

To a concentrated solution of NaN₃ (40 g) in water (100 ml), a solutionof trimethyltin chloride (20 g) in dioxane (10 ml) was added in threeportions under vigorous stirring. An instantaneous precipitate formationwas observed. The mixture, after stirring overnight at room temperature,was filtered. The residue was washed with water, and dried under suctionand the in vacuo over P₂ O₅.

Yield 18.7 g (81%), mp 132°-136° C.

Step 3: N-Triphenylmethyl-5-(4'-bromomethyl-biphen-2-yl)tetrazole

The titled compound was prepared starting from 2-cyano-4'-methylbiphenyl(Step 1) as described in European Patent Application EP 0,291,969.

EXAMPLE 32-butyl-3-[(2'-Carboxybiphenyl-4-yl)methyl]-3H-imidazo[4,5-b]pyridine

Step 1: Preparation of 2-butylimidazo[4,5-b]pyridine

A mixture of valeric acid (5.50 mL, 50.4 mmol), 2,3-diaminopyridine (5.0g, 45.8 mmol), and polyphosphoric acid (50 g) was heated to 100° C. withstirring for 5 hours. Basification (NH₄ OH), extraction (EtOAc, 4×20mL), drying (K₂ CO₃), and concentration gave 7.61 g (95%) of the titlecompound as an amorphous tan solid which was judged pure by ¹ H NMR andtlc (mp ca 80° C. without recrystallization).

Step 2: Preparation of2-Butyl-3-[(2'-carboxybiphen-4-yl)methyl]-3H-imidazo[4,5-b]pyridine

Part A

To a stirred suspension of NaH (104 mg of an 80% dispersion, 3.45 mmol)in dry dimethylformamide (8 mL) at room temperature was added2-butylimidazo[4,5-b]pyridine (504 mg, 2.88 mmol). After 30 minutes,tert-butyl-4'-bromomethylbiphenyl-2-carboxylate (1.0 g, 2.88 mmol) wasadded in one portion. After 15 hours, the excess NaH was quenched withwater (0.5 mL) and the bulk of the DMF was evaporated in vacuo at40°-50° C. A total of two runs at this scale were combined for thefollowing purification. Extraction with EtOAc (5×20 mL) from brine (5mL), drying (K₂ CO₃), concentration, and purification (flashchromatography, SiO₂, 100% EtOAc) gave 925 mg (36%) of2-butyl-3-((2'-tert-butoxycarbonyl)biphen-4-yl)methylimidazo[4,5-b]pyridineas a thick oil: Rf=0.7 (SiO₂, 100% EtOAc);

¹ H NMR (250 MHz, CDCl₃) δ8.36 (dd, 1H, J=4.8, 1.4 Hz), 8.01 (dd, 1H,J=7.9, 1.4 Hz), 7.76 (dd, 1H, J=7.6, 1.9 Hz), 7.52-7.36 (m, 2H)7.28-7.18 (m, 6H), 5.58 (s, 2H), 2.85 (t, 2H, J=7.6 Hz, 1.92-1.81 (m,2H), 1.52-1.48 (m, 2H), 1.19 (s, 9H), 0.95 (t, 3H, J=7.3 Hz).

Part B

To a solution of the above tert-butyl ester (820 mg, 1.85 mmol) inmethylene chloride (30 mL) at rt was added trifluoroacetic acid (4 mL).After 18 hours, the solution was evaporated (from benzene) andchromatographed (Sephadex-LH-20, MeOH) to give 680 mg (95%) of the titlecompound as a white solid: mp 181°-183° C. (EtOAc).

¹ H NMR (250 MHz, CDCl₃) δ8.35 (dd, 1H, J=4.8, 1.1 Hz), 8.05 (dd, 1H,J=8, 1.3 Hz), 7.91 (d, 1H, J=7.3 Hz), 7.54-7.08 (m, 8H), 5.48 (s, 2H),2.67 (t, 2H, J=7.5 Hz), 1.57-1.42 (m, 2H), 1.21-1.07 (m, 2H), 0.65 (t,3H, J=7.3 Hz).

EXAMPLE 42-Butyl-1-(2'-carboxybiphen-4-yl)methyl-1H-imidazo[4,5-b]pyridine

Part A

The isomer2-butyl-1-(2'-tert-butoxycarbonylbiphen-4-yl)methyl-1H-imidazo[4,5-b]pyridinewas obtained from Part A of Example 3.

Yield: (153 mg, 6%) Rf=0.15 (SiO₂, 100% EtOAc, 2 elutions); ¹ H NMR (250MHz, CDCl₃) δ8.50 (dd, 1H, J=5, 1.2 Hz), 7.78 (dd, 1H, J=8.5, 1.5 Hz),7.54-7.35 (m, 3H), 7.39-7.22 (M, 3H), 7.12-7.02 (m, 3H), 5.39 (s, 2H),2.92 (t, 2H, J=8 Hz), 1.97-1.84 (m, 2H), 1.53-1.38 (m, 2H), 1.20 (s,9H), 0.93 (t, 3H, J=7 Hz). The third isomer,4-(2'-carboxybiphen-4-yl)methyl-2-butyl-4H-imidazo[4,5-b]pyridine (414mg) was obtained from Part A of Example 3 and was characterized by MS,1H NMR and NOE.

Part B

The title compound was prepared according to the procedure described inPart B, Example 3.

Yield 85 mg (85%) of an amorphous solid (mp. >260° C.).

EXAMPLE 52-Butyl-3-(2'-carboxybiphen-4-yl)methyl-3H-imidazo[4,5-c]pyridine

Step 1: Preparation of 2-butylimidazo[4,5-c]pyridine

The title compound was prepared according to the procedure described forthe preparation of 2-butylimidazo[4,5-b]pyridine starting with3,4-diaminopyridine.

Yield: 3.69 g (92%) thick oil.

¹ H NMR (300 MHz, CDCl₃) δ8.93 (s, 1H), 8.35 (d, 1H, J=6 Hz), 7.48 (d,1H, J=6 Hz), 3.01 (t, 2H, J=7 Hz), 1.92-1.82 (m, 2H), 1.48-1.30 (m, 2H),0.86 (t, 3H, J=7 Hz).

Step 2: Preparation of2-Butyl-3-(2'-carboxybiphen-4-yl)methyl-3H-imidazo[4,5-c]pyridine

Part A

2-butyl-3-[(2'-tert-butoxycarbonylbiphen-4-yl)methyl]-2-butyl-3H-imidazo[4,5-c]pyridinewas prepared according to the procedure described in Example 1, Part Afrom 2-butylimidazo[4,5-c]pyridine (220 mg, 1.25 mmol), tert-butyl4'-bromomethylbiphenyl-2-carboxylate (414 mg, 1.19 mmol), and NaH (1.88mmol).

Yield: 25 mg (5%) thick oil; Rf: 0.45 (SiO₂ tlc, 1% MeOH/EtOAc).

¹ H NMR (250 MHz, CDCl₃) δ8.66 (s, 1H), 8.42 (d, 1H, J=5.6 Hz), 7.78(dd, 1H, J=7.5, 1.4 Hz), 7.66 (d, 1H, J=5.5 Hz), 7.52-7.35 (m, 2H),7.31-7.24 (m, 3H), 7.10 (d, 2H, J=8 Hz), 5.46 (s, 2H), 2.92 (t, 2H,J=7.5 Hz), 1.97-1.80 (m, 2H), 1.55-1.39 (m, 2H), 1.21 (s, 9H), 0.96 (t,3H, J=7.3 Hz).

Part B

The title compound was prepared according to the procedure described inPart B, Example 1.

Yield: 24 mg (104%) of an oil.

¹ H NMR (300 MHz, CD₃ OD) δ9.28 (s, 1H), 8.52 (d, 1H, J=5.3 Hz), 8.13(d, 1H, 5.5 Hz), 7.82 (d, 1H, J=7.5 Hz), 7.56 (t, 1H, 7.5 Hz), 7.46 (t,1H, 7.5 Hz), 7.40-7.32 (m, 3H), 7.24 (d, 2H, J=7 Hz), 5.73 (s, 2H), 3.05(t, 2H, J=7 Hz), 1.92-1.78 (m, 2H), 1.54-1.40 (m, 2H), 0.95 (t, 3H, J=7Hz).

EXAMPLE 6 Preparation of1-(2'-carboxybiphen-4-yl)methyl-2-butyl-1H-imidazo[4,5-c]pyridine Part A

The isomer1-(2'-tert-butoxycarbonylbiphen-4-yl)methyl-2-butyl-1H-imidazo[4,5-b]pyridinewas obtained from Part A of Example 5.

Yield: 32 mg thick oil; Rf=0.40 (SiO₂ tlc, 1% MeOH/EtOAc).

¹ H NMR (250 MHz, CDCl₃) δ9.07 (s, 1H), 8.35 (d, 1H, J=5.6 Hz), 7.77(dd, 1H, J=7.5, 1.3 Hz), 7.51-7.35 (m, 2H), 7.33-7.22 (m, 3H), 7.18 (d,1H, J=5.6 Hz), 7.06 (d, 2H, J=8 Hz), 5.39 (s, 2H), 2.90 (t, 2H, J=7.5Hz), 1.93-1.80 (m, 2H), 1.53-1.37 (m, 2H), 1.22 (s, 9H), 0.96 (t, 3H,J=7.2 Hz).

The isomer5-(2'-tert-butoxycarbonylbiphen-4-yl)methyl-2-butyl-5H-imidazo[4,5-b]pyridine154 mg) was also obtained from Part A of Example 5 and was characterizedby MS, ¹ H NMR and NOE.

Part B

The title compound was prepared according to the procedure described inPart B, Example 3.

Yield: 28 mg of an oil.

¹ H NMR (300 MHz, CD₃ OD) δ9.21 (s, 1H), 8.54 (d, 1H, J=6 Hz), 8.31(d,1H, J=6 Hz), 7.82 (d, 1H, J=7 Hz), 7.55 (t, 1H, J=7 Hz), 7.44 (t,1H), J=7 Hz), 7.38-7.31 (m, 3H), 7.23 (d, 2H, J=8 Hz), 5.74 (s, 2H) 3.08(t, 2H, J=7.5 Hz), 1.82-1.78 (m, 2H), 1.53-1.42 (m, 2H), 0.95 (t, 3H,J=7.6 Hz).

EXAMPLE 72-Butyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridinePart A

To a stirred suspension of NaH (102 mg of an 80% dispersion, 3.39 mmol)in dry dimethylformamide (6 mL) at rt was added2-butylimidazo[4,5-b]pyridine (495 mg, 2.83 mmol) in one portion. After20 minutes, the mixture was cooled to 0° C. andN-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl)tetrazole (1.50 g, 2.70mmol) was added in one portion. The resulting dark colored mixture waswarmed to rt and stirred for 15 hours. The excess NaH was quenched withwater (1 mL) and the bulk of the DMF was removed in vacuo at 40°-50° C.Extraction with EtOAc (4×20 mL) from brine (60 mL), drying (K₂ CO₃), andconcentration gave a thick dark oil. Purification by flashchromatography (SiO₂, solvent gradient: 80% EtOAc/hexanes, 100% EtOAc)gave 417 mg (23%) of2-butyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-1H-imidazo[4,5-b]pyridine as a thick oil: Rf=0.75 (SiO₂, 100% EtOAc).

¹ H NMR (300 MHz, CDCl₃) δ8.35 (1H, dd, J=6, 1 Hz), 8.05 (1H, dd, J=9, 1Hz), 7.92 (1H, dd, J=9, 1.5 Hz), 7.51-7.42 (3H, m), 7.36-7.20 (11H, M),7.07 (2H, d, 7 Hz), 6.96-6.89 (7H, m), 5.40 (2H, s), 2.73 (2H, t, J=7.5Hz), 1.84-1.70 (2H, m), 1.41-1.30 (2H, m), 0.88 (3H, t, J=7.5 Hz).

Part B

To a stirred solution of the above trityl-protected tetrazole (140 mg,0.215 mmol) in glacial HOAc (4 mL) at rt was added water (4 mL). Themixture was heated to 80° C. for 2 hours, then stirred for 15 hours atrt. The solvent was removed in vacuo (35° C.) and the residue waschromatographed (SiO₂, 80:20:1 CH₂ Cl₂ --MeOH--NH₄ OH) to give 66 mg(75% of the title compound as an off-white amorphous solid:

¹ H NMR (300 MHz, CD₃ OD) δ8.33 (1H, dd, J=4.5, 1.5 Hz), 8.00 (1H, dd,J=8, 1.5 Hz) 7.56 (2H, apparent tm, J=8 Hz) 7.47 (2H, apparent tm, J=8H)7.32 (1H, dd, J=4.5, 8 Hz) 7.07 (apparent singlet, 4H), 5.55 (2H, s),2.86 (2H, t, J=8 Hz), 1.75-1.63 (2H, m) 1.45-1.32 (2H, m), 0.91 (3H, t,7.5 Hz).

EXAMPLE 8 Preparation of2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Step 1: Preparation of 2-propylimidazo[4,5-b]pyridine

The title compound was prepared according to the procedure described forthe preparation of 2-butylimidazo[4,5-b]pyridine starting with3,4-diaminopyridine and butyric acid. Yield: 6.60 g (89%) amorphoussolid.

Step 2: Preparation of2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Part A

2-propyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)-biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridinewas prepared according to the procedure described in Example 7, Part Afrom 2-propylimidazo[4,5-b]pyridine (19 mg, 0.118 mmol),N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (60 mg, 0.108mmol), and NaH (0.236 mmol).

Yield: 18 mg (26%) thick oil; Rf: 0.75 (SiO₂ tlc, 100% EtOAc).

¹ H NMR (300 MHz, CDCl₃) δ8.27 (dd, 1H, J=6, 1 Hz), 8.01 (dd, 1H, J=9, 1Hz), 7.85 (dd, 1H, J=9, 1.5 Hz), 7.50-7.42 (m, 2H), 7.38-7.22 (m, 11H),7.08 (d, 2H J=7 Hz), 6.98-6.88 (m, 7H), 5.40 (s, 2H), 2.66 (t, 2H, J=7.5Hz), 1.80-1.65 (m, 2H), 0.93 (t, 3H, J=6 Hz).

Part B

The title compound was prepared according to the procedure described inExample 7, Part B.

Yield: 10 mg (95%) of an amorphous solid.

¹ H NMR (300 MHz, CD₃ OD) δ8.33 (d, 1H, J=5 Hz), 7.99 (d, 1H, J=8 Hz),7.58 (t, 2H, J=7.5 Hz), 7.48 (t, 2H, J=7.5 Hz), 7.33 (dd, 1H, J=5, 8Hz), 7.06 (apparent singlet, 4H), 5.56 (s, 2H), 2.84 (t, 2H, J=8 Hz),1.83-1.68 (m, 2H), 0.98 (t, 3H, J=6 Hz).

EXAMPLE 97-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl-7-3H-imidazo[4,5-b]pyridine

Step 1: Preparation of 7-methyl-2-propylimidazo[4,5-b]pyridine

A mixture of butyric acid (6.57 mL, 71.9 mmol), 2,3-diamino-4-picoline(8.05 g, 65.4 mmol) (Lappin, G. R., Slezak, F. B. J. Am. Chem. Soc.(1950) 72, 7806-7) and polyphosphoric acid (50 g) was heated to 100° C.with stirring for 3 hours. The reaction was monitored by tlc of NH₄ OHneutralized aliquots. Basification (NH₄ OH), extraction (CH₂ Cl₂, 4×50mL), drying (K₂ CO₃), purification (by filtering through 100 g SiO₂,EtOAc elution), and concentration gave 10.0 g (95%) of the titlecompound as an amorphous tan solid which was judged pure by ¹ H NMR andtlc: mp 110°-112° C. (without recrystallization).

¹ H NMR (300 MHz, CDCl₃) δ8.13 (d, 1H, J=5 Hz), 7.01 (d, 1H, J=5 Hz),3.01 (t, 2H, J=7.8 Hz), 2.67 (s, 3H), 2.07-1.93 (m, 2H), 1.06 (t, 3H,J=7.5 Hz).

Step 2:7-methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pryidine

Part A

3-[2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl]methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridinewas prepared according to the procedure described in Example 7, Part Afrom 2-propyl-7-methylimidazo[4,5-b]pyridine (991 mg, 5.66 mmol),N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (3.0 g, 5.39mmol), and NaH (6.47 mmol).

Yield: 1.11 g (32%) thick oil; Rf: 0.80 (SiO₂ tlc, 1:1 EtOAc-hexanes.

¹ H NMR (300 MHz, CDCl₃) δ8.20 (d, 1H, J=5 Hz), 7.89 (d, 1H, J=8 Hz),7.51-7.39 (m, 2H), 7.38-7.20 (m, 10H), 7.10-7.03 (m, 3H), 6.95-6.88, (m,8H), 5.49 (s, 2H), 2.78-2.68 (m, 2H), 2.69 (s, 3H), 1.83-1.60 (m, 2H),0.91 (t, 3H, J=5.5 Hz).

Part B

The title compound was prepared according to the procedure described inExample 7, Part B from 1.01 g of the above prepared compound.

Yield: 583 (92%) of an amorphous solid. mp: 195°-197° C. (EtOAc).

¹ H NMR (300 MHz, CD₃ OD) δ8.16 (d, 1H, J=5 Hz), 7.60-7.38 (m, 4H), 7.12(d, 1H, J=5 Hz), 7.09 (apparent singlet, 4H), 5.52 (s, 2H), 2.83 (t, 2H,J=5 Hz), 2.64 (s, 3H), 1.79-1.60 (m, 2H), 0.95 (t, 3H, J=5.5 Hz).

Anal. Calcd for C₂₄ H₂₃ N₇.0.25 H₂ O: C, 69.63; H, 5.72; N, 23.68.Found: C, 69.75; H, 5.58; N, 23.69.

Sodium and potassium salts were prepared by combining the product withone equivalent of NaOH or KOH and recrystallization of the resultingsalt from the solvent indicated.

7-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)-biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinesodium salt

mp: >250° C. (EtOAc); ¹ H NMR (300 MHz, CD₃ OD) δ8.17 (d, 1H, J=5 Hz),7.53-7.37 (m,4H), 7.20 (d, 1H, J=5 Hz), 7.08 (d, 2H, J=8.3 Hz), 7.00 (d,2H, J=8.3 Hz), 5.51 (s, 2H), 2.84 (t, 2H, J=7.5 Hz), 2.65 (s, 3H,1.79-1.62 (m, 2H), 0.96 (t, 3H, J=7.5 Hz).

7-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)-biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinepotassium salt

mp: >250° C. (acetone/hexanes); ¹ H NMR (300 MHz, CD₃ OD) δ8.17 (d, 1H,J=5 Hz), 7.52-7.37 (m, 4H), 7.13 (d, 1H, J-5 Hz), 7.08 (d, 2H, J=8.3Hz), 6.99 (d, 2H, J=8.3 Hz), 5.51 (s, 2H), 2.84 (t, 2H, J=7.5 Hz), 2.65(s, 3H), 1.79-1.62 (m, 2H), 0.96 (t, 3H, J=7.5 Hz).

EXAMPLE 10 Preparation of2-butyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Step 1: Preparation of 6-bromo-2-butyl-7-methylimidazo[4,5-b]pyridine

The title compound was prepared according to the procedure described forthe preparation of 2-butylimidazo[4,5-b]pyridine starting with5-bromo-2,3-diamino-4-picoline.

Yield: 2.54 g (95%) of an amorphous solid.

¹ H NMR (250 MHz, CDCl₃) δ8.45 (s, 1H), 3.05 (t, 2H, J=7 Hz), 2.73 (s,3H), 2.02-1.87 (m, 2H), 1.61-1.45 (m, 2H), 1.02 (t, 3H, J=7 Hz).

Step 2: Preparation of 2-butyl-7-methylimidazo[4,5-b]pyridine

To a cooled (-78° C.) stirred solution of6-bromo-2-butyl-7-methylimidazo[4,5-b]pyridine (98 mg, 0.366 mmol) inTHF (4 mL) was added tert-butyllithium (0.86 mL of a 1.7M solution inpentane, 1.46 mmol). After 15 minutes, MeOH (0.5 mL and brine were addedthe mixture was warmed to room temperature and extracted with EtOAc(4×10 mL). Drying (K₂ CO₃), concentration, and purification (SiO₂, 100%EtOAc) gave 60 mg (87%) of the title compound as an oil.

¹ H NMR (300 MHz, CDCl₃) δ8.18 (d, 1H, J=5 Hz), 7.08 (d, 1H, J=5 Hz),3.05 (t, 2H, J=7.6 Hz), 2.72 (s, 3H), 2.03-1.89 (m, 2H), 1.62-1.43 (m,2H), 0.96 (t, 3H, J=7.8 Hz).

Step 3: Preparation of2-butyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Part A

2-Butyl-7-methyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridinewas prepared according to the procedure described in Example 7, Part Afrom 2-butyl-7-methylimidazo[4,5-b]pyridine (28 mg, 0.148 mmol),N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl)tetrazole (62 mg, 0.135mmol), and NaH (0.296 mmol).

Yield: 16 mg (16%) thick oil; Rf: 0.80 (SiO₂ tlc, 90% EtOAc/hexanes).

¹ H NMR (300 MHz, CDCl₃) δ8.22 (d, 1H, J=5 Hz), 7.92 (d, 1H, J=8 Hz),7.54-7.41 (m, 2H), 7.38-7.20 (m, 10H), 7.11-7.04 (m, 3H), 6.97-6.88 (m,8H), 5.40 (s, 2H), 2.76-2.68 (m, 2H), 2.71 (s, 3H), 1.74-1.63 (m, 2H),1.42-1.30 (m, 2H), 0.91 (t, 3H, J=5.5 Hz).

Part B

The title compound was prepared according to the procedure described inExample 7, Part B.

Yield: 8.5 mg (89%) of an amorphous solid.

¹ H NMR (300 MHz, CD₃ OD) δ8.17 (d, 1H, J=5 Hz), 7.59-7.42 (m, 4H), 7.15(d, 1H, J=5 Hz), 7.10-7.01 (m, 4H), 5.52 (s, 2H), 2.86 (t, 2H, J=8 Hz),2.66 (s, 3H), 1.71-1.59 (m, 2H), 1.45-1.30 (m, 2H), 0.90 (t, 3H, J=7Hz).

EXAMPLE 118-Butyl-1,3-dimethyl-7-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-1,2,3,6-tetrahydro-2,6-dioxopurine

Step 1: Preparation of8-Butyl-1,3-dimethyl-1,2,3,6-tetrahydro-2,6-dioxopurine

To 3.00 g (17.6 mmol) 5,6-diamino-1,3-dimethyluracil hydrate (Aldrich)in a 50 mL round bottom flask was added 2.31 mL (2.17 g, 21.2 mmol, 1.2eq) valeric acid and sufficient polyphosphoric acid to make the flaskapproximately half-full. The viscous mixture was heated at 50°-60° for14 hours with periodic agitation.

The mixture was cooled, diluted with 30 mL distilled water and the pHadjusted to 8-9 (paper) by the slow addition of concentrated ammoniumhydroxide (approx. 20 mL). A tan precipitate formed and was removed byfiltration. The filtrate was extracted with chloroform (5×) and theextracts combined with the tan precipitate, dried (MgSO₄), filtered andsolvents removed in vacuo. The pale yellow residue was chromatographedon silica gel, eluting with ethyl acetate. In this manner, 2.16 g (9.14mmol, 52%) of the title compound was obtained as a fluffy, white solid.

NMR (300 MHz, DMSO-d₆): 0.89 (t, 3H), 1.30 (m, 2H), 1.66 (m, 2H), 2.68(t, 2H), 3.23 (s, 3H), 3.42 (s, 3H).

FAB-MS: 237 (M+H, 100%).

FAB-MS: 237 (M+H, 100%).

Step 2: Preparation of8-Butyl-1,3-dimethyl-7-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-1,2,3,6-tetrahydro-2,6-dioxopurine

To a solution of 100 mg (0.42 mmol) of purine from Step 1, in 2 mL dryDMF at room temperature was added 20 mg of 60% sodium hydride-oildispersion (12 mg NaH, 0.50 mmol, 1.2 eq). After 15 minutes, a solutionof 226 mg (0.41 mmol, 0.96 eq)N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole in 1 mL dry DMFwas added and the mixture stirred at room temperature 16 hours.

The reaction mixture was added to 30 mL ethyl acetate and washed with 5%aqueous citric acid (2×), saturated aqueous sodium bicarbonate (1×) andbrine (1×). The organic layer was separated, dried (MgSO₄), filtered andsolvents removed in vacuo. The residue was purified by medium pressureliquid chromatography on silica gel, eluting with ethyl acetate/hexane(2:1), to afford 246 mg (0.35 mmol, 82%) of the trityl intermediate as awhite solid.

NMR (300 MHz, CDCl₃ : 0.87 (t, 3H), 1.30 (m, 2H), 1.61 (m, 2H), 2.57 (t,2H), 3.37 (s, 3H), 3.58 (s, 3H), 5.43 (s, 2H), 6.8-7.8 (severalmultiplets, 23H).

FAB-MS: 712 (M+H, 1%), 471 (M-trityl, 7%), 243 (trityl, 100%).

The intermediate described above (50 mg, 0.07 mmol) was treated with 2mL of 50% aqueous acetic at room temperature for 16 hours with vigorousstirring. All volatiles were removed in vacuo, and the residue purifiedby reverse-phase HPLC on a C18 column eluting with methanol/0.1% aqueoustrifluoroacetic acid (linear gradient: 85% MeOH increased to 95% MeOHover 10 minutes). In this manner, 17 mg (0.04 mmol, 57%) of the titlecompound was obtained as a colorless glass.

NMR (300 MHz, DMSO-d₆): 0.81 (t, 3H), 1.26 (m, 2H), 1.50 (m, 2H), 2.66(t, 2H), 3.23 (s, 3H), 3.42 (s, 3H), 5.58 (s, 2H), 7.07 (d, 2H), 7.13(d, 2H), 7.5-7.7 (m, 4H).

FAB-MS: 471 (M+H, 100%).

EXAMPLE 12 Preparation of9-(2'-Carboxybiphen-4-yl)methyl-6-chloro-8-propylpurine

Step 1: 6-Chloro-4,5-diaminopyrimidine

To a cold solution of 5-amino-4,6-dichloropyrimidine (2.0 g, 12.2 mmol)in isopropanol (20 ml) was added liquid ammonia (5 ml), and the mixturewas transferred into a sealed tube. The tube was heated at 130° C. for 3hours and then cooled to room temperature. The product precipitated outwas filtered and dried in vacuo. Yield 2.0 g (quantitative).

Step 2: 6-Chloro-8-propylpurine

To a solution of 4,5-diamino-6-chloropyrimidine (0.289 g, 2 mmol) in2-methoxyethanol (10 ml) were added trimethylorthobutyrate (0.5 ml, 3mmol) and p-toluenesulfonic acid (0.03 g), and the mixture was refluxedfor 18 hours and then concentrated in vacuo. The residue was partitionedbetween water and and ethylacetate. The organic phase was then washedwith brine and dried (MgSO₄). The crude product obtained afterevaporation of the solvent was purified by flash column chromatographyon silica-gel using ethylacetate/hexane (1:1). The fractions containingpure product were pooled and concentrated in vacuo, and then allowed tostand at room temperature overnight. The crystalline product wasfiltered and dried.

Yield 0.17 g (43%).

NMR (CDCl₃): δ1.05 (t, J=9 Hz, 3H), 2.0 (q, 2H), 3.1 (q, 2H), 8.74 (s,1H); FAB mass-spectra: m/e 197 and 199. (M+H).

Analysis calculated for C₈ H₉ N₄ Cl: C, 48.86; H, 4.61; N, 28.50. Found:C, 49.06; H, 4.76; N, 28.30

Step 3: 6-Chloro-8-propyl-9-(2'-t-butoxycarbonylbiphen-4-yl)methylpurine

To a suspension of NaH (0.20 g) in dry DMF (3 ml),6-chloro-8-propyl-purine (0.06 g, 0.3 mmol) was added, and the mixturewas stirred at 40° C. for 20 minutes.t-Butyl-4-bromomethylbiphenyl-2'-carboxylate (0.11 g, 0.31 mmol) wasthen added at room temperature and stirring continued for 3 hours at 40°C. The content of the flask was poured into ice-water (100 ml andextracted with ethylacetate. The organic phase was separated and driedover MgSO₄. Removal of the solvent under reduced pressure gave the crudeproduct which was then purified by flash-chromatography on silica-gelusing ethylacetate-hexane (1:1). The pure titled compound was obtainedas a glass-like solid (0.073 g, 53%).

NMR (CDCl₃): δ1.04 (t, J=9 Hz, 3H), 1.213 (s, 9H), 1.91 (m, 2H), 2.89(t, 2H), 5.52 (s, 2H), 7.15-7.52 (m, 7H), 7.79 (dd, J₁ =8 Hz and J₂ =2Hz, 1H), 8.72 (s, 1H); FAB-MS: m/e 463 and 465 (M+H).

Step 4: 6-Chloro-8-propyl-9-(2'-carboxybiphen-4-yl)methylpurine

To a solution of the above t-butyl ester (0.070 g, 0.15 mmol) inmethylene chloride (3 ml), anhydrous trifluoracetic acid (2 ml) andanisole (0.02 ml) were added. After stirring for 3 hours at roomtemperature, the mixture was evaporated to dryness. The crude productwas purified by flash-chromatography on silica-gel usingchloroform-methanol-NH₄ OH (40:10:1).

Yield 0.034 g (56%).

NMR(CD₃ OD): δ0.99 (t, J=9 Hz, 3H), 1.78 (m, 2H), 2.94 (t, 2H), 5.624(s, 2H), 7.20-7.58 (m, 7H), 7.79 (d, J₁ =8 Hz, 1H), 8.72 (s, 1H);FAB-MS: m/e 407 and 409 (M+H).

Analysis calculated for C₂₂ H₁₉ N₄ O₂ Cl.0.25H₂ O: C, 64.23; H, 4.77; N,13.62. Found: C, 64.09; H, 4.86; N, 13.27.

EXAMPLE 13 Preparation of8-Butyl-9-[(2'-carboxybiphen-4-yl)methyl]-6-chloropurine

Step 1: 8-Butyl-6-Chloropurine

A mixture of 6-Chloro-4,5-diaminopyrimidine (0.289 g, 2 mmol) (from Step1 of Example 12), trimethylorthovalerate (0.52 ml, 3 mmol) and p-TsOH(0.04 g) in 2-methoxyethanol (10 ml) was refluxed for 24 hours. Theproduct was isolated and purified as described in Step 2 of Example 12to give the crystalline titled compound (0.113 g, 23%).

NMR (CDCl₃): δ0.997 (t, J=9 Hz, 3H), 1.484 (m, 2H), 1.925 (m, 2H), 3.075(m, 2H), 7.27 (s, 1H) and 8.723 (s, 1H).

FAB-MS: m/e 211 and 213 (M+H).

Analysis calculated for C₉ H₁₁ N₄ Cl: C, 51.31; H, 5.26; N, 26.60.Found: C, 51.34; H, 5.30, N, 26.46.

Step 2: 8-Butyl-6-Chloro-9-(2'-t-butoxycarbonylbiphen-4-yl)methylpurine

The titled compound was prepared by the alkylation of 6-chloro-8-butylpurine (0.063 g, 0.3 mmol) witht-Butyl-4-bromomethylbiphenyl-2'-carboxylate (0.104 g, 0.3 mmol)according to the procedure described in Step 3 of Example 12. Afterflash-chromatographic purification of the crude product using ethylacetate-hexane (1:1), the product was obtained as a foam (0.085 g, 60%).

NMR (CDCl₃): δ0.946 (t, J=9 Hz, 3H), 1.26 (s, 9H), 1.464 (m, 2H), 1.86(m, 2H), 2.91 (m, 2H), 5.51 (s, 2H), 7.16-7.51 (m, 7H), 7.78 (m, 1H) and8.723 (s, 1H).

FAB-MS: m/e 477 and 479 (M+H).

Step 3: 8-butyl-6-Chloro-9-(2'-carboxybiphen-4-yl)methylpurine

The t-butyl ester (0.080 g) was deprotected according to the proceduredescribed in Step 4 of Example 12. The pure product was obtained aftercrystallization from methanol-ether.

Yield 0.030 g (42%).

NMR (CD₃ OD): δ0.91 (t, J=9 Hz, 3H), 1.41 (m, 2H), 1.76 (m, 2H), 2.98(m, 2H), 5.63 (s, 2H), 7.2-7.6 (m, 7H), 7.8 (d, J=8 Hz, 2H), 8.715 (s,1H).

FAB-MS: m/e 421 and 423 (M+H).

Analysis calculated for C₂₃ H₂₁ N₄ O₂ Cl.0.2H₂ O: C, 65.07; H, 5.08; N,13.20. Found: C, 65.23; H, 5.44; N, 12.80.

EXAMPLE 14 Preparation of8-Butyl-9-(2'-carboxybiphen-4-yl)methyl-6-hydroxypurine

In Step 3 of Example 13, the title compound was isolated as the minor(10%) by product of the reaction. The compound is presumed to arise fromthe mucleophillic displacement of the 6-chloro function of the purinewith water. The structure was confirmed by NMR (CD₃ OD): δ0.886 (m, 3H),1.35 (m, 2H), 1.64 (m, 2H), 2.79 (m, 2H), 5.50 (s, 2H), 7.2-7.6 (m, 7H),7.79 (m, 2H), 8.051 (s, 1H) and mass spectral analysis.

FAB-MS: m/e 403 (M+H).

Analysis calculated for C₂₃ H₂₂ N₄ O₃ : C, 68.66; H, 5.47; N, 13.93.Found: C, 68.32; H, 5.52; N, 14.07.

EXAMPLE 15 Preparation of6-Chloro-8-propyl-9-(2'-tetrazol-5-yl)biphen-4-yl)methylpurine

Step 1:6-Chloro-8-propyl-9-(2'-(N-triphenylmethyltetrazole-5-yl)biphen-4-yl)methylpurine

To a stirred suspension of NaH (0.016 g of a 60% dispersion in oil, 0.4mmol) in dry dimethylformamide (1.5 ml) was added6-Chloro-8-propylpurine (0.044 g, 0.25 mmol) at room temperature. After20 minutes, the mixture was cooled to 0° C. andN-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (0.139 g, 0.25mmol) was added. The resulting mixture was warmed to room temperatureand then stirred at 40° C. for 3 hours. The reaction was cooled, and thecontent of the flask was poured into ice-water (50 ml) and extractedwith ethyl acetate (3×15 ml). The combined organic phase was washed withbrine and then dried over anhydrous Na₂ SO₄. Removal of the solvent gavethe crude product as a foam which was purified by flash-chromatographyon silica-gel using ethyl acetate/hexane (1:3).

Yield 0.07 g (foam).

NMR (CDCl₃): δ0.96 (t, J=8 Hz, 3H), 1.806 (m, 2H), 2.75 (m, 2H), 5.35(s, 2H), 6.85-7.54 (m, 22H), 7.85 (m, 1H), 8.72 (s, 1H).

FAB-MS: m/e 674 and 676 (M+H).

Step 2: 6-Chloro-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine

The trityl protected compound (0.065 g) obtained above was dissolved in50% aqueous acetic acid (2 ml) and the mixture was heated at 50° C. for15 hours. The solvent was removed in vacuo and residue was purified byflash chromatography on silica-gel using chloroform-methanol-NH₄ OH(40:10:1) to give pure desired product as a glass like solid (0.016 g).

NMR (CD₃ OD): δ0.98 (t, J=8 Hz, 3H), 1.754 (m, 2H), 2.89 (m, 2H), 5.57(s, 2H), 7.135 (q, 4H), 7.5-7.7 (m, 5H), 8.70 (s, 1H).

FAB-MS: m/e 431 and 433 (M+H).

Analysis calculated for C₂₂ H₁₉ N₈ Cl: C, 61.27; H, 4.41; N, 25.99.Found: C, 61.47; H, 4.78; N, 26.32.

EXAMPLE 16 Preparation of5,7-Dimethyl-2-ethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Step 1: 2-Amino-4,6-dimethyl-3-nitropyridine

2-Amino-4,6-dimethylpyridine (10.0 g, 81.8 mmol) was added portion-wiseto 65 mL of H₂ SO₄ (conc. d=1.84) which was stirred (mechanical) at 0°C. After complete addition, the mixture was warmed to room temperatureuntil the mixture became homogeneous. The solution was then cooled to-10° C. and a pre-cooled (0° C.) mixture of concentrated HNO₃ (11.5 mL,d=1.40) and H₂ SO₄ (8.2 mL, d=1.84) was added at such a rate as not toraise the internal reaction temperature above -9° C. Ten minutes afterthe addition was complete this cooled (-10° C.) mixture was poured onto400 g of crushed ice. The resulting slurry was neutralized by theaddition of conc NH₄ OH (to pH 5.5) while cooling (ice bath). The solidwas isolated by filtration, and dried at room temperature to give 13.3 gof 2-nitramino-4,6-dimethylpyridine as a white solid.

To 75 mL of stirred conc H₂ SO₄ cooled to -5° C. (ice-salt bath) wasadded 4,6-dimethyl-2-nitraminopyridine (13.2 g, 79 mmol) portion-wise atsuch a rate as to maintain the internal temperature below -3° C. Themixture was warmed to 0° C. until homogeneous (30 minutes) at which timetlc (SiO₂, 1:1 EtOAc/hexanes on a NH₄ OH neutralized aliquot) indicatedthat the rearrangement was complete. The mixture was poured onto 400 gof crushed ice and the pH was adjusted to 5.5 by the addition ofconcentrated NH₄ OH. The resulting yellow slurry was cooled to 0° C.,filtered, washed with cold water (50 mL), and dried at room temperatureto give 10.32 g of a mixture of the title compound and the 5-nitroisomer in a 55:45 ratio (determined by ¹ H NMR). This mixture was useddirectly in Step 2.

Step 2: 5,7-Dimethyl-2-ethylimidazo[4,5-b]pyridine

To a mixture of 8.44 g of a 55:45 mixture of2-Amino-3-nitro-4,6-dimethylpyridine and2-Amino-4,6-dimethyl-5-nitropyridine in MeOH (1.2 L) was added 10% Pd/C(2.4 g). The reaction vessel was evacuated then purged with H₂ at 1 atm.and stirred vigorously for 18 hours. Filtration (celite), andconcentration gave 6.65 g of a mixture of2,3-diamino-4,6-dimethylpyridine and 2,5-diamino-4,6-dimethylpyridine asa dark solid. To 5.40 g (39.4 mmol) of this mixture was added propionicacid (8.80 mL, 118 mmol) followed by polyphosphoric acid (100 mL). Thisstirred mixture was heated to 90° C. for 3 hours then to 100° C. for 1hour. After the reaction was complete, the warm mixture was poured onto300 g of ice and the mixture was made basic with NH₄ OH. The mixture wasextracted (4×50 mL CH₂ Cl₂), dried (K₂ CO₃) and concentrated to give amixture of the title compound and4,6-dimethyl-2,5-bis(propionamido)pyridine. Purification (SiO₂, 5%MeOH/EtOAc) gave 1.66 g of the title compound as the slower elutingcomponent.

¹ H NMR (CD₃ OD, 300 MHz) δ6.95 (s, 1H), 2.92 (q, 2H, J=7.8 Hz), 2.54(apparent s, 6H), 1.40 (t, 3H, J=7.8 Hz)

Step 3:5,7-Dimethyl-2-ethyl-3-(2'-(tetrazol-5-yl)-biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Part A

5,7-Dimethyl-2-ethyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridinewas prepared according to the procedure described in Example 7, Part Afrom 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (1.51 g, 8.62 mmol),N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (5.29 g, 9.48mmol), and NaH (17.2 mmol).

Yield: 4.25 g white solid.

¹ H NMR (300 MHz, CDCl₃) δ7.86 (dd, 1H, J=7, 2 Hz), 7.50-7.41 (m, 2H),7.36-7.21 (m, 10H), 7.05 (d, 2H, J=4.5 Hz), 6.95-6.89 (m, 7H), 6.86 (d,2H, J=4.5 Hz), 5.35 (s, 2H), 2.67 (q, 2H, J=7.5 Hz), 2.65 (s, 3H), 2.58(s, 3H), 1.25 (t, 3H, J=7.5 Hz).

Part B

To a stirred solution of the tritylprotected tetrazole (4.13 g, 6.33mmol) in CH₂ Cl₂ (40 mL) at room temperature was added 85% formic acid(60 mL). After 45 minutes, the mixture was concentrated and the residuewas purified by chromatography (SiO₂, 85:13.5:1.5 CHCl₃ --MeOH--NH₄ OH)followed by crystallization from 30 mL of MeOH to give 2.18 g (84%)solid: mp 156°-158° C.

¹ H NMR (300 MHz, CD₃ OD) δ7.68-7.61 (m, 2H), 7.57-7.50 (m, 2H), 7.07(apparent singlet, 4H), 7.04 (s, 1H), 5.55 (s, 2H), 2.85 (q, 2H, J=7.5Hz), 2.61 (s, 3H), 2.58 (s, 3H), 1.25 (t, 3H, J=7.5 Hz).

Anal. Calcd for C₂₄ H₂₃ N₇.0.25 H₂ O: C, 69.63; H, 5.72; N, 23.68.Found: C, 69.91; H, 5.73; N, 23.60.

Another crystalline form (momohydrate, mp 186° C.) was produced whencrystallized from 10% water-methanol.

Sodium or potassium salts can be prepared as described in Example 9.

EXAMPLE 17 Preparation of5,7-Dimethyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared as described in Example 16 using butyricacid in the place of propionic acid in Step 2.

FAB MS, M³⁰ +1=424.

¹ H NMR (300 MHz, CD₃ OD) δ7.67-7.60 (m, 2H), 7.56-7.49 (m, 2H), 7.07(apparent singlet, 4H), 7.04 (s, 1H), 5.55 (s, 2H), 2.81 (t, 2H, J=7.8Hz), 2.60 (s, 3H), 2.58 (s, 3H), 1.73-1.60 (m, 2H), 0.95 (t, 3H, J=7.5Hz).

EXAMPLE 18 Preparation of2-Butyl-5,7-dimethyl-3-(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared as described in Example 16 using valericacid in the place of propionic acid in Step 2.

FAB MS, M⁺ +1=438.

¹ H NMR (300 MHz, CD₃ OD) δ7.67-7.60 (m, 2H), 7.56-7.49 (m, 2H), 7.07(apparent singlet, 4H), 7.04 (s, 1H), 5.55 (s, 2H), 2.81 (t, 2H, J=7.8Hz), 2.60 (s, 3H), 2.58 (s, 3H), 1.73-1.60 (m, 2H), 0.95 (t, 3H, J=7.5Hz).

EXAMPLE 19 Preparation of3-(2'-Carboxybiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridinePart A

3-(2'-tert-Butoxycarbonylbiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridinewas prepared according to the procedure described in Example 3, Part Afrom 5,7-dimethyl-2-ethylimidazo[4,5-c]pyridine (50 mg, 0.28 mmol),tert-butyl 4'-bromomethylbiphenyl-2-carboxylate (109 mg, 0.314 mmol),and NaH (0.417 mmol).

Yield: 96 mg thick oil after chromatography (SiO₂, 50% EtOAc/hexanes.

FAB MS, M⁺ +1=442.

Part B

The title compound was prepared according to the procedure described inExample 3, Part B.

Yield: 80 mg.

FAB MS: M⁺ +1=386.

¹ H NMR (300 MHz, CD₃ OD) δ7.71 (dd, 1H, J=7.2, 1.2 Hz), 7.52-7.30 (m,5H), 7.15 (d, 2H, J=8.4 Hz), 7.04 (s, 1H), 5.60 (s, 2H), 2.88 (q, 2HJ=7.5 Hz), 2.62 (s, 3H), 2.59 (s, 3H), 1.31 (t, 3H, J=7.5 Hz).

EXAMPLE 20 Preparation of5-Amino-2-propyl-3-(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Step 1: 5-Butyramido-2-propylimidazo[4,5-b]pyridine

A mixture of 2,6-diamino-3-nitropyridine (878 mg, 5.7 mmol) and Pd-C(10%, 100 mg) in MeOH (100 mL) was stirred under 1 atm. H₂ for 16 hours.The mixture (containing the air sensitive triamine) was filtered,evaporated, and to this flask was added polyphosphoric acid (15 mL) andbutyric acid (1.05 mL, 11.5 mmol). This mixture was heated to 80° C. for5 hours, cooled to room temperature, diluted with water and neutralizedwith concentrated NH₄ OH. Extractive workup (CH₂ Cl₂) gave 345 mg of5-(butyramido)-2-propylimidazo[4,5-b]pyridine.

¹ H NMR (300 MHz, CDCl₃) δ7.94 (d, 1H, J=8.5 Hz), 7.65 (d, 1H, J=8.5Hz), 2.96 (t, 2H J=7.5 Hz), 2.30 (t, 2H J=7 Hz), 1.98-1.84 (m, 2H),1.68-1.55 (m, 2H), 0.99 (t, 3H, J=7.5 Hz), 0.80 (t, 3H, J=7.0 Hz).

Step 2: 5-amino-2-propylimidazo[4,5-b]pyridine

A mixture of 5-butyramido-2-propylimidazo[4,5-b]pyridine (250 mg, 1.07mmol), MeOH (20 mL), and concentrated aqueous HCl (2 mL) was heated to45° C. for 16 hours. Concentration and neutralization with NaHCO₃ gave150 mg of the title compound as a glass.

¹ H NMR (300 MHz, CD₃ OD) δ7.57 (d, 1H, J=8.5 Hz), 6.46 (d, 1H, J=8.5Hz), 2.76 (t, 2H, J=7.5 Hz), 1.85-1.70 (m, 2H), 0.93 (t, 3H, J=7.5 Hz).

Step 3:5-amino-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Part A

5-amino-2-propyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridinewas prepared according to the procedure described in Example 7, Part Afrom 5-amino-2-propylimidazo[4,5-b]pyridine (130 mg, 0.80 mmol),N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (445 mg, 0.800mmol), and NaH (2.4 mmol).

Yield: 185 mg (as a glass like solid).

Part B

A mixture of the triphenymethyl tetrazolate described in Part A (80 mg,0.122 mmol), concentrated aqueous HCl (1 mL), in methanol (10 mL) wasstirred for 16 h at room temperature. Concentration and purification(SiO₂, 80:19:1 CH₂ Cl₂ :MeOH:NH₄ OH) gave 50 mg of the title compound asa white solid.

FAB MS M⁺ +1=411.

¹ H NMR (300 MHz, CD₃ OD) δ7.67 (d, 1H, J=8.7 Hz), 7.61-7.55 (m, 2H),7.51-7.43 (m, 2H), 7.07 (apparent s, 4H), 6.58 (d, 1H, J=8.7 Hz), 5.42(s, 2H), 2.76 (t, 2H J=7.5 Hz), 1.73-1.60 (d, 2H), 0.93 (t, 3H, J=7.2Hz).

EXAMPLE 21 Preparation of2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Step 1: 2-Ethyl-7-methylimidazo[4,5-b]pyridine

A mixture of propionic acid (0.89 ml, 12 mmols), 2,3-diamino-4-picoline(1.23 g, 10 mmol) and polyphosphoric acid (40 g) was heated to 100° C.for 6 hours. Work-up of the reaction and purification of the crudeproduct according to the procedure described in Step 1 of Example 9 gavethe desired compound (1.46 g, 90%) as a tan colored solid.

¹ H NMR (300 MHz, CDCl₃): 8.14 (d, 1H, J=5 Hz), 7.01 (d, 1H, J=5 Hz),3.02 (q, 2H, J=7.8 Hz), 2.69 (s, 3H), 1.45 (t, 3H, J=7.8 Hz).

Step 2:2-Ethyl-7-methyl-3-(2'-tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Part A:

2-Ethyl-7-methyl-3(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridinewas prepared according to the procedure described in Part A of Example7, from 2-ethyl-7-methylimidazo[4,5-b]pyridine (0.5 g, 3.11 mmol),N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl)tetrazole (1.82 g, 3.26mmol) and NaH (3.12 mmol). The crude product (1.9 g, foam) was purifiedby flash chromatography on silica-gel using EtOAc-hexanees (1:1.5) togive the desired product as a white solid (0.95 g, 47.5%).

¹ H NMR (300 MHz, CDCl₃): 8.2 (d, 1H, J=5 Hz), 7.9 (d, 1H, J=8 Hz),6.80-7.55 (m, 23H), 5.4 (s, 2H), 2.58-2.85 (m, 5H), 1.25 (t, 3H, J=7.8Hz).

Part B:

The title compound was prepared from the above compound (0.42 g)according to the procedure described in Part B of Example 7. Yield: 0.26g (99%). The material was finally crystallized from methanol-ether togive white crystalline product (0.24 g). mp: 192°-193° C.

¹ H NMR (300 MHz, CD₃ OD): 8.2 (d, 1H, J=5 Hz), 7.4-7.62 (m, 4H),6.96-7.45 (m, 5H), 5.52 (s, 2H), 2.88 (q, 2H, J=7.8 Hz), 2.65 (s, 3H),1.27 (t, 3H, J=7.8 Hz).

Anal. Calcd. for C₂₃ H₂₁ N₇. 0.5 H₂ O: C, 68.32; H, 5.45; N, 24.26.Found: C, 68.59; H, 5.73; N, 24.12.

EXAMPLE 22 Preparation of2,7-dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Step 1: 2,7-Dimethylimidazo[4,5-b]pyridine

The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2mmol) and acetic acid (0.15 ml) according to the procedure described inStep 1 of Example 9. The crude product was purified by flashchromatography on silica-gel using EtOAc-MeOH (9:1) to give the pureproduct (0.25 g, 85%) as a light brown solid.

¹ H NMR (300 MHz, CDCl₃): 8.14 (d, 1H, J=5 Hz), 7.01 (d, 1H, J=5 Hz),2.73 (s, 3H), 2.62 (s, 3H).

Step 2:2,7-Dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The titled compound was prepared from the above compound according tothe procedures described in Part A and Part B of Example 5. The puredesired product was obtained as a white amorphous powder.

¹ H NMR (300 MHz, CD₃ OD): 8.12 (d, 1H, J=5 Hz), 7.45-7.65 (m, 4H),6.96-7.4 (m, 5H), 5.52 (s, 2H), 2.65 (s, 3H), 2.52 (s, 3H).

Anal. Calcd. for C₂₂ H₁₉ N₇.H₂ O: C, 77.19; H, 5.26; N, 24,56. Found: C,76.91; H, 5.73; N, 24.33.

EXAMPLE 23 Preparation of7-Methyl-2-pentyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Step 1: 7-Methyl-2-pentyl-imidazo[4,5-b]pyridine

The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2mmol) and hexanoic acid (0.25 ml, 2 mmols) according to the proceduredescribed in Step 1 of Example 9. The crude product was purified byflash chromatography on silica-gel using EtOAc-MeOH (9:1) to give thepure product (0.28 g, 69%) as a tan colored solid.

¹ H NMR (300 MHz, CDCl₃): 8.17 (d, 1H, J=5 Hz), 7.05 (d, 1H, J=5 Hz),3.03 (t, 2H, J=7.8 Hz), 2.70 (s, 3H), 1.32-2.1 (m, 6H), 0.92 (t, 3H,J=7.8 Hz).

Step 2:7-Methyl-2-pentyl-3-(2'-(tetrazol-5-yl)-biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The titled compound was prepared from the above compound according tothe procedures described in Part A and Part B of Example 7. The puredesired product was obtained as a white amorphous powder (R_(f) 0.45 inCHCl₃ -MeOH-NH₄ OH 40:10:1).

¹ H NMR (300 MHz, CD₃ OD): 8.20 (d, 1H, J=5 Hz), 7.48-7.80 (m, 4H),7.01-7.3 (m, 5H), 5.72 (s, 2H), 2.84 (t, 2H, J=7.8 Hz), 2.65 (s, 3H),1.68 (m, 2H), 1.32 (m, 4H), 0.9 (t, 3H, J=7.8 Hz).

FAB-MS: m/e 438 (M+H).

EXAMPLE 24 Preparation of7-methyl-2-nonyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Step 1: 7-Methyl-2-nonylimidazo[4,5-b]pyridine

The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2mmol) and decanoic acid (0.35 g, 2 mmol) according to the proceduredescribed in Step 1 of Example 9. The crude product was purified byflash chromatography on silica-gel using EtOAc-MeOH (20:1) to give thepure product (0.38 g, 72%) as a tan colored solid.

¹ H NMR (300 MHz, CDCl₃): 8.16 (d, 1H, J=5 Hz), 7.05 (d, 1H, J=5 Hz),3.03 (t, 2H, J=7.8 Hz), 2.69 (s, 3H), 1.25-2.0 (m, 14H), 0.90 (t, 3H,J=7.8 Hz).

Step 2:7-methyl-2-nonyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The titled compound was prepared from the above compound according tothe procedures described in Part A and Part B of Example 7. The puredesired product was obtained as a cream colored amorphous powder (R_(f)0.5 in CHCl₃ -MeOH-NH₄ OH 40:10:1).

¹ H NMR (300 MHz, CD₃ OD): 8.20 (d, 1H, J=5 Hz), 7.48-7.70 (m, 4H),7.08-7.3 (m, 5H), 5.58 (s, 2H), 2.84 (t, 2H, J=7.8 Hz), 2.64 (s, 3H),1.68 (m, 2H), 1.1-1.4 (m, 12H), 0.89 (t, 3H, J=7.8 Hz).

FAB-MS: m/e 494 (M+H).

EXAMPLE 25 Preparation of2-Isopropyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Step 1: 2-Isopropyl-7-methylimidazo[4,5-b]pyridine

The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2mmol) and isobutyric acid (0.19 ml, 2 mmol) according to the proceduredescribed in Step 1 of Example 9. The crude product was purified byflash chromatography on silica-gel using EtOAc-MeOH (20:1) to give thepure product (0.25 g, 72%) as a tan colored solid.

¹ H NMR (300 MHz, CDCl₃): 8.21 (d, 1H, J=5 Hz), 7.05 (d, 1H, J=5 Hz),3.40 (m, 1H), 2.71 (s, 3H), 1.55 (d, 6H, J=7 Hz).

FAB-MS: m/e 176 (M+H).

Step 2:2-Isopropyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The titled compound was prepared from the above compound according tothe procedures described in Part A and Part B of Example 7. The puredesired product was obtained as a cream colored amorphous powder (R_(f)0.45 in CHCl₃ -MeOH-NH₄ OH 40:10:1).

¹ H NMR (300 MHz, CD₃ OD): 8.20 (d, 1H, J=5 Hz), 7.50-7.70 (m, 4H),7.08-7.2 (m, 5H), 5.6 (s, 2H), 3.3 (m, 1H), 2.68 (s, 3H), 1.3 (d, 6H,J=7 Hz).

FAB-MS: m/e 410 (M+H).

EXAMPLE 26 Preparation of7-Methyl-2-(3-methyl)propyl-3-(2'-(tetrazol-5-yl)-biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Step 1: 7-Methyl-2-(3-methyl)propyl)imidazo[4,5-b]pyridine

The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2mmol) and 3-methylbutyric acid (0.22 ml, 2 mmol) according to theprocedure described in Step 1 of Example 9. The crude product waspurified by flash chromatography on silica-gel using EtOAc-MeOH (20:1)to give the pure product (0.30 g, 78%) as a tan colored solid.

¹ H NMR (300 MHz, CDCl₃): 8.20 (d, 1H, J=5 Hz), 7.05 (d, 1H, J=5 Hz),2.90 (d, 2H, J=7 Hz), 2.70 (s, 3H), 2.32 (m, 1H), 1.11 (d, 6H, J=7 Hz).

FAB-MS: m/e 190 (M+H).

Step 2:7-methyl-2-(3-methyl)propyl-3-(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The titled compound was prepared from the above compound according tothe procedures described in Part A and Part B of Example 7. The puredesired product was obtained as a cream colored amorphous powder.

¹ H NMR (300 MHz, CD₃ OD): 8.20 (d, 1H, J=5 Hz), 7.50-7.70 (m, 4H),7.08-7.2 (m, 5H), 5.6 (s, 2H), 2.75 (d, 2H, J=7 Hz), 2.68 (s, 3H), 2.1(m, 1H), 0.92 (d, 6H, J=7 Hz).

FAB-MS: m/e 424 (M+H).

EXAMPLE 27 Preparation of2-Cyclopropyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared as described in Example 9 usingcyclopropane carboxylic acid in place of butyric acid in Step 1.

¹ H NMR (300 MHz, CD₃ OD): 8.14 (d, 1H, J=5 Hz), 7.50-7.70 (m, 4H),7.08-7.2 (m, 5H), 5.64 (s, 2H), 2.61 (s, 3H), 2.12 (m, 1H), 1.11 (m,4H).

FAB-MS: m/e 408 (M+H).

EXAMPLE 28 Preparation of2-Methoxymethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Step 1: 2-Methoxymethyl-7-methylimidazo[4,5-b]pyridine

A mixture of 2,3-diamino-4-picoline (0.1 g, 0.81 mmol) and methoxyaceticacid (0.16 ml, 2 mmol) was heated in a sealed tube at 165° C. for 24hours. The reaction was cooled and neutralized with NH₄ OH. The crudematerial was dissolved in methanol (2 ml) and silica-gel (10 g) wasadded. The dried silica-gel was then loaded on a silica-gel flash-columnand eluted initially with EtOAc and then with 2% methanol in EtOAc. Thepure desired compound was obtained as a cream colored solid (0.067 g,47%).

¹ H-NMR (CDCl₃): 8.27 (d, 1H, J=5 Hz), 7.07 (d, 1H, J=5 Hz), 4.86 (s,2H), 3.57 (s, 3H), 2.7 (s, 3H).

FAB-MS: m/e 178 (M+H).

Step 2:2-Methoxymethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared from the compound described in Step 1 asdescribed in Step 2 of Example 9.

¹ H NMR (300 MHz, CD₃ OD): 8.26 (d, 1H, J=5 Hz), 7.50-7.71 (m, 4H),7.05-7.26 (m, 5H), 5.61 (s, 2H), 4.64 (s, 2H), 3.32 (s, 3H), 2.67 (s,3H).

FAB-MS: m/e 412 (M+H).

EXAMPLE 29 Preparation of8-Propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine

6-Chloro-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine (0.030g) was dissolved in ethanol (2 ml) and was stirred under an atmosphereof hydrogen in presence of Pd-C(10%) (0.01 g) for 24 hours. The catalystwas filtered off and the filtrate was evaporated to dryness giving thepure desired product as a glass like solid (0.020 g).

NMR(CD₃ OD): δ1.0 (t, 3H, J=7.4 Hz), 1.8 (m, 2H), 2.88 (t, 2H, J=7.4Hz), 5.56 (s, 2H), 7.1-7.34 (m, 5H), 7.45-7.7 (m, 4H), 8.90 (s, 1H),8.98 (s, 1H).

FAB-MS: m/e 397 (M+H).

Analysis calculated for C₂₂ H₂₀ N₈ : C, 66.00; H, 5.00; N, 28.00. Found:C, 65.57; H, 5.34; N, 27.67.

EXAMPLE 30 Preparation of8-Butyl-6-chloro-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine

The titled compound was prepared from 8-butyl-6-chloropurine accordingto the procedures described in Example 15.

NMR(CD₃ OD): δ0.92 (t, J=8 Hz, 3H), 1.42 (m, 2H), 1.75 (m, 2H), 2.92 (m,2H), 5.58 (s, 2H), 7.14 (m, 4H), 7.5-7.7 (m, 5H), 8.72 (s, 1H).

FAB-MS: m/e 445 and 447 (M+H).

Analysis calculated for C₂₃ H₂₁ N₈ Cl: C, 62.09; H, 4.72; N, 25.20.Found: C, 61.79; H, 4.95; N, 25.32.

EXAMPLE 31 Preparation of8-Butyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine

The titled compound was prepared from8-Butyl-6-chloro-9-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-purine asdescribed in Example 29.

NMR (CD₃ OD): δ0.99 (t, 3H, J=7.4 Hz), 1.30 (m, 2H), 1.78 (m, 2H), 2.88(t, 2H, J=7.4 Hz), 5.55 (s, 2H), 7.1-7.3 (m, 5H), 7.45-7.63 (m, 4H),8.90 (s, 1H), 8.98 (s, 1H).

FAB-MS: m/e 411 (M+H).

Analysis calculated for C₂₃ H₂₂ N₈ : C, 67.32; H, 5.37; N, 27.32. Found:C, 67.76; H, 5.54; N, 27.67.

EXAMPLE 32 Preparation of2-Chloro-6-methyl-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine

Step 1: 2-Chloro-6-methyl-8-propylpurine

A mixture of 2-Chloro-4,5-diamino-6-methylpyrimidine (0.80 g, 5.04mmol), trimethylorthobutyrate (1.2 ml, 7.6 mmol) and p-TsOH (0.08 g) in2-methoxyethanol (24 ml) was heated in an oil bath at 140° C. for 24hours. The product was isolated as described in Step 2 of Example 12 andpurified by flash chromatography using EtOAc-hexane (1:1) to give thecrystalline titled compound (0.5 g, 47%).

NMR(CDCl₃): δ1.03 (t, J=8 Hz, 3H), 1.9 (q, 2H), 2.82 (s, 3H), 3.0 (t,J=8 Hz, 2H).

FAB-MS: m/e 211 and 213 (M+H).

Analysis calculated for C₉ H₁₁ N₄ Cl: C, 51.31; H, 5.26; N, 26.60.Found: C, 51.43; H, 5.50, N, 26.81.

Step 2:2-Chloro-6-methyl-8-propyl-9-(2'-(tetrazol-5-yl)-biphen-4-yl)methylpurine

The titled compound was prepared from 2-Chloro-6-methyl-8-propylpurine(from Step 1) according to the procedure described in Example 15.

NMR(CD₃ OD): δ0.97 (t, J=8 Hz, 3H), 1.73 (q, 2H), 2.77 (s, 3H), 2.82 (t,J=8 Hz, 2H), 5.52 (s, 2H), 7.1-7.3 (m, 4H), 7.5-7.75 (m, 5H).

FAB-MS: m/e 445 and 447 (M+H).

Analysis calculated for C₂₃ H₂₁ N₈ Cl: C, 62.09; H, 4.72; N, 25.20.Found: C, 61.79; H, 4.95; N, 25.32.

EXAMPLE 33 Preparation of2-Dimethylamino-6-methyl-8-propyl-9-(2'-(tetrazol-5-yl)-biphen-4-yl)methylpurine

Step 1: 2-Dimethylamino-6-methyl-8-propylpurine

To a solution of 2-Chloro-6-methyl-8-propylpurine (from Step 1 ofExample 32) (0.1 g, 0.47 mmol) in ethanol (2 ml) was added condenseddimethylamine (1 ml) at 0° C. The mixture was then placed in asteel-bomb and heated at 110° C. for 7 hours. The reaction was cooledand the mixture was concentrated in vacuo. The residue was partitionedbetween CHCl₃ and water, and the organic was separated and dried overMgSO₄. The crude product obtained after removal of the solvent waspurified by flash-chromatography on silica-gel using 5% MeOH in CHCl₃giving the titled compound as an amorphous solid (0.065 g, 64%).

NMR(CDCl₃): δ1.01 (t, J=8 Hz, 3H), 1.8 (q, J=8 Hz, 2H), 2.65 (s, 3H),2.8 (t, J=8 Hz, 2H), 3.2 (s, 6H).

FAB-MS: m/e 220 (M+H).

Step 2:2-Dimethylamino-6-methyl-8-propyl-9-(2'-(tetrazol-5-yl)-biphen-4-yl)methylpurine

The title compound was prepared from2-Dimethylamino-6-methyl-8-propylpurine (from Step 1) according to theprocedures described in Example 15.

NMR(CD₃ OD): δ0.95 (t, J=8 Hz, 3H), 1.66 (q, J=8 Hz, 2H), 2.61 (s, 3H),2.75 (t, J=8 Hz, 2H), 3.2 (s, 6H), 5.36 (s, 2H), 7.07-7.23 (m, 4H),7.5-7.7 (m, 5H).

FAB-MS: m/e 454 (M+H) and 476 (M+Na).

EXAMPLE 34 Preparation of6-Methyl-2-methylamino-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine

Step 1: 6-Methyl-2-methylamino-8-propylpurine

To a solution of 2-Chloro-6-methyl-8-propylpurine (from Step 1 ofExample 32) (0.1 g, 0.47 mmol) in ethanol (2 ml) was added condensedmethylamine (1 ml) at -20° C. The mixture was then placed in asteel-bomb and heated at 110° C. for 7 hours. The reaction was cooledand the mixture was concentrated in vacuo. The residue was partitionedbetween CHCl₃ and water, and the organic layer was separated and driedover MgSO₄. The crude product obtained after removal of the solvent waspurified by flash-chromatography on silica-gel using 5% MeOH in CHCl₃giving the titled compound as an amorphous solid (0.115 g,quantitative).

NMR(CDCl₃): δ1.03 (t, J=8 Hz, 3H), 1.8 (q, J=8 Hz, 2H), 2.64 (s, 3H),2.8 (t, J=8 Hz, 2H), 3.0 (d, J=5 Hz, 3H), 5.1 (br s, 1H).

FAB-MS: m/e 206 (M+H).

Step 2:6-Methyl-2-methylamino-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine

The titled compound was prepared from6-Methyl-2-methylamino-8-propylpurine (from Step 1) according to theprocedures described in Example 15.

NMR(CD₃ OD): δ0.90 (t, J=8 Hz, 3H), 1.62 (q, J=8 Hz, 2H), 2.5 (s, 3H),2.65 (t, J=8 Hz, 2H), 2.88 (s, 3H), 5.26 (s, 2H), 7.02 (s, 4H), 7.3-7.5(m, 5H).

FAB-MS: m/e 440 (M+H).

EXAMPLE 35 Preparation of6-Methyl-2-(morpholin-4-yl)-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine

Step 1: 6-Methyl-2-(morpholin-4-yl)-8-propylpurine

A solution of 2-Chloro-6-methyl-8-propylpurine (from Step 1 of Example32) (0.1 g, 0.47 mmol) in morpholine (2 ml) was placed in a steel-bomb,and the mixture was heated at 122° C. for 18 hours. The reaction wascooled, and the mixture was concentrated in vacuo. The residue wasdissolved in CHCl₃ (2 ml) and was purified by flash-chromatography onsilica-gel using 5% MeOH in CHCl₃ giving the titled compound as anamorphous solid (0.1 g, 87%).

NMR(CDCl₃): δ1.03 (t, J=8 Hz, 3H), 1.8 (q, J=8 Hz, 2H), 2.65 (s, 3H),2.82 (t, J=8 Hz, 2H), 3.8 (s, 8H).

FAB-MS: m/e 262 (M+H).

Step 2:6-Methyl-2-(morpholin-4-yl)-8-propyl-9-(2'-(tetrazol-5-yl)biphen-4-yl)methylpurine

The titled compound was prepared from6-Methyl-2-(N-morpholino)-8-propylpurine (from Step 1) according to theprocedures described in Example 15.

NMR(CD₃ OD): δ0.90 (t, J=8 Hz, 3H), 1.62 (q, J=8 Hz, 2H), 2.54 (s, 3H),2.68 (t, J=8 Hz, 2H), 3.7 (m, 8H), 5.29 (s, 2H), 7.05 (m, 4H), 7.4-7.6(m, 5H).

FAB-MS: m/e 496 (M+H).

EXAMPLE 36 Preparation of3-(2'-carboxybiphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridin

7-Methyl-2-propylimidazo[4,5-b]pyridine (described in Example 9) wasalkylated with 2-t-butoxycarbonyl-4'-bromomethylbiphenyl and theresulting protected derivatives was deprotected according to theprocedure described in Step 2 of Example 3.

NMR (CDCl₃): δ0.93 (t, J=7.5 Hz, 3H), 1.69 (q, 2H), 2.63 (s, 3H), 2.78(t, J=7.5 Hz, 2H), 5.49 (s, 3H), 7.04-7.5 (m, 8H), 7.8 (d, J=2.4 Hz,1H), 8.14 (d, J=5 Hz, 1H).

FAB-MS: m/e 386 (M+H).

EXAMPLE 37 Preparation of7-Methyl-3-(2'-(N-(phenylsulfonyl)carboxamido-biphen-4-yl)methyl-2-propyl-3H-imidazo[4,5-b]pyridine

To a suspension of3-(2'-carboxybiphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine(0.1 g, 0.26 mmol) in dry THF (5 ml) was added 1,1'-carbonyldiimidazole(0.042 g, 0.26 mmol), and the mixture was refluxed for 3 hours and thencooled to room temperature. Benzenesulfonamide (0.05 g, 0.33 mmol) andDBU (0.49 ml, 0.33 mmol) were added and the mixture was stirred at 40°C. for 7 hours. The reaction was cooled and concentrated in vacuo. Theresidue was dissolved in water (5 ml) and acidified with 10% aqueousNaH₂ PO₄ to pH 5 and extracted with EtOAc (3×20 ml). The combinedorganic phase was dried over MgSO₄ and concentrated in vacuo to give thecrude product, which was then purified by flash-chromatography onsilica-gel using 2% MeOH in EtOAc to give the desired product as whiteamorphous solid (0.087 g, 64%).

NMR (CDCl₃): δ1.0 (t, J=7.5 Hz, 3H), 1.8 (q, 2H), 2.7 (s, 3H), 2.78 (t,J=7.5 Hz, 2H), 5.50 (s, 3H), 6.8-7.8 (m, 14H), 8.2 (d, J=5 Hz, 1H).

FAB-MS: m/e 525 (M+H).

EXAMPLE 38 Preparation of3-(2'-(N-(4-(Chloro)phenylsulfonylcarboxamido)biphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared from3-(2'-carboxybiphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridineand p-chlorobenzenesulfonamide according to the procedure described inExample 37.

NMR (CD₃ OD): δ0.99 (t, J=7.5 Hz, 3H), 1.76 (m, 2H), 2.69 (s, 3H), 2.87(t, J=7.5 Hz, 2H), 5.60 (s, 3H), 6.95 (d, J=8 Hz, 2H), 7.1-7.8 (m, 11H),8.25 (d, J=5 Hz, 1H).

FAB-MS: m/e 559 and 561 (M+H).

Analysis calculated for C₃₀ H₂₇ N₄ O₃ ClS: C, 64.46; H, 4.83; N, 10.03.Found: C, 64.78; H, 5.07; N, 10.26.

EXAMPLE 39 Preparation of3-(2'-(Methylsulfonylcarboxamido)biphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine

To a suspension of3-(2'-carboxybiphenyl-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine(0.1 g, 0.26 mmol) in dry THF (5 ml) was added 1,1'-carbonyldiimidazole(0.042 g, 0.26 mmol), and the mixture was refluxed for 3 hours and thencooled to room temperature. A solution of sodium salt ofMethanesulfonamide [prepared from methanesulfonamide (0.036 g, 0.39mmol) and NaH (0.39 mmol) in DMF (1.5 ml) at 40° C.] was then added, andthe mixture was stirred at 40° C. for 8 hours. The reaction was cooledand concentrated in vacuo. The residue was dissolved in water (5 ml) andacidified with 10% aqueous NaH₂ PO₄ to pH 5 and extracted with EtOAC(3×20 ml). The combined organic phase was dried over MgSO₄ andconcentrated in vacuo to give the crude product, which was then purifiedby flash-chromatography on silica-gel using 2% MeOH in EtOAc to give thedesired product as white amorphous solid (0.05 g, 42%).

NMR (CD₃ OD): δ0.99 (t, J=7.5 Hz, 3H), 1.77 (m, 2H), 2.67 (s, 3H), 2.90(t, J=7.5 Hz, 2H), 2.98 (s, 3H), 5.62 (s, 3H), 7.14-7.27 (m, 3H),7.37-7.6 (m, 6H), 8.2 (d, J=5 Hz, 1H).

FAB-MS: m/e 463 (M+H).

EXAMPLE 40 Preparation of2-Cyclopropyl-5,7-dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared as described in Example 16 usingcyclopropane carboxylic acid in place of propionic acid in Step 2.

¹ H NMR (CD₃ OD; 300 MHz): δ1.08 (m, 4H), 2.06 (m, 1H), 2.55 (s, 3H),2.56 (s, 3H), 5.63 (s, 2H), 6.99 (s, 1H), 7.10 (m, 4H), 7.49-7.63 (m,4H).

FAB-MS: m/e 422 (M+H).

Preparation of7-Methyl-2-propyl-3-(2'trifluoromethylsulfonamidobiphen-4-yl)methyl-3H-imidazo-[4,5-b]pyridineEXAMPLE 41

Step 1: 4-Methyl-2'-nitrobiphenyl

A 1 L three-necked 24/40 round-bottom flask equipped with a mechanicalstirrer, a 250 mL constant pressure addition funnel with a nitrogeninlet at the top, and a septum was flame dried, cooled and then chargedwith a solution of 29.07 g (0.17 mol) of p-bromotoluene in 100 mL ofanhydrous tetrahydrofuran under a nitrogen atmosphere. The solution wasstirred and cooled to -78° C. and 200 mL (0.34 mol) of a 1.7M solutionof t-butyllithium in pentane was added via the addition funnel over 30minutes. When the addition was complete, the cooling bath was removedand the reaction mixture was stirred for 30 minutes and allowed to warmto room temperature. The dropping funnel was next charged with 170 mL(0.17 mol) of a 1.0M solution of zinc chloride in diethylether which wasadded to the reaction mixture over a 10 minute period. A separate 1 Lthree-necked 24/40 round-bottom flask equipped with a mechanicalstirrer, a nitrogen inlet and a septum, was flame dried, cooled and thencharged with 4.04 g (6.0 mmol) of bis(triphenylphosphine)palladium(II)chloride and 50 mL of anhydrous tetrahydrofuran under a nitrogenatmosphere. The stirrer was started and 8.0 mL of a 1.5M solution (12mmol) of diisobutylaluminum hydride in toluene was added to thesuspension via syringe. The catalyst was stirred an additional 10minutes at room temperature, and then a solution of 23.23 g (0.115 mol)of 1-bromo-2-nitrobenzene in 100 mL of anhydrous tetrahydrofuran wasadded. The suspension of the tolylzinc chloride was then transferred tothe second flask via a wide diameter cannula. The reaction mixture wasstirred an additional 45 minutes at room temperature, then most of thetetrahydrofuran was removed on a rotary evaporator. The resulting oilwas partitioned between ethyl acetate and 1.0N hydrochloric acid. Theorganic layer was washed successively with water and brine, then dried(MgSO₄), filtered and evaporated. The residual oil was purified on asilica gel flash chromatography column eluted with 10% ethylacetate-hexane to afford after evaporation and drying in vacuo 15.43 g(63%) of the product as a viscous yellow oil:

NMR (CDCl₃): δ2.36 (s, 3H), 7.16-7.24 (m, 4H), 7.38-7.46 (m, 2H),7.55-7.62 (m, 1H), 7.80 (d, J=10 Hz, 1H).

MS (FAB) m/e 214 (MH⁺).

Step 2: 4-Bromomethyl-2'-nitrobiphenyl

A 2 L 24/40 three necked round-bottom flask equipped with a mechanicalstirrer, a reflux condenser and a stopper, was charged with 15.427 g (72mmol) of 4-methyl-2'-nitro[1,1'-biphenyl], 1.2 L of carbontetrachloride, 14.164 g (80 mmol) of N-bromosuccinimide, and 0.50 g of2,2'-azobis(2-methylpropionitrile). The stirred reaction mixture wasrefluxed under a nitrogen atmosphere for 4 hours, then cooled to roomtemperature and filtered. The filtrate was evaporated in vacuo and theresidual oil was purified on a silica gel flash chromatography columneluted with 10% ethyl acetate-hexane. Evaporation of the pure fractionsafforded the product as a yellow crystalline solid (7.83 g, 37%) whichhad: mp 109°-110° C.

NMR (CDCl₃): δ4.52 (s, 2H), 7.24-7.30 (m, 2H), 7.40-7.52 (m, 4H),7.58-7.65 (m, 1H), 7.86 (d, J=10 Hz, 1H).

MS (FAB) m/e 294 (MH⁺).

Step 3:7-Methyl-3-[(2'-nitrobiphen-4-yl)methyl]-2-propyl-3H-imidazo[4,5-b]pyridine

To a solution of 0.913 g (5.2 mmol) of7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine in 10 mL of anhydrousdimethylformamide was added 0.210 g (5.7 mmol) of a 60% mineral oildispersion of sodium hydride. The reaction mixture was magneticallystirred under a nitrogen atmosphere for 2 hours, at which point 1.675 g(5.7 mmol) of 4-bromomethyl-2'-nitrobiphenyl was added as a solid. Thereaction mixture was stirred an additional 1 hour at room temperature,then partitioned between ethyl acetate and water. The organic layer wasextracted, washed with brine, dried (MgSO₄), filtered and evaporated.The residual oil was purified on a silica gel flash chromatographycolumn eluted with 75% ethyl acetate-hexane, which after evaporation ofthe pure fractions and drying in vacuo afforded 1.009 g (50%) of theproduct as a tan solid.

NMR (CDCl₃) δ0.97 (t, J=8 Hz, 3H), 1.70-1.83 (m, 2H), 2.66 (s, 3H), 2.81(t, J=10 Hz, 2H), 5.52 (s, 2H), 7.02 (d, J=6 Hz, 1H), 7.14-7.25 (m, 4H),7.36 (d, J=10 Hz, 1H), 7.42-7.48 (m, 1H), 7.56-7.61 (m, 1H), 7.82 (d,J=10 Hz, 1H), 8.20 (d, J=6 Hz, 1H).

MS (FAB) m/e 387 (MH⁺).

Step 4:3-(2'-Aminobiphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine

To a solution of 0.475 g (1.23 mmol) of7-methyl-3-[(2'-nitrobiphen-4-yl)methyl]-2-propyl-3H-imidazo[4,5-b]pyridinein 15 mL of absolute ethanol was added 50 mg of 10% palladium on carboncatalyst and the mixture was hydrogenated at 40 psig of hydrogen on aParr apparatus. Reduction was complete after 1 hour and the reactionmixture was filtered and evaporated in vacuo to afford a tan solid(0.416 g, 95%) which was used in the subsequent step without furtherpurification.

NMR (CDCl₃) δ0.98 (t, J=8 Hz, 3H), 1.70-1.86 (m, 3H), 2.66 (s, 3H), 2.83(t, J=10 Hz, 2H), 3.64-3.72 (br s, 2H), 5.52 (s, 2H), 6.70-6.82 (m, 2H),7.00-7.19 (m, 5H), 7.36 (d, J=10 Hz, 2H), 8.20 (d, J=6 Hz, 1H).

MS (FAB) m/e 357 (MH⁺).

Step 5:7-Methyl-2-propyl-3-(2'-trifluoromethylsulfonamidobiphen-4-yl)methyl-3H-imidazo[4,5-b]-pyridine

To a magnetically stirred solution of 0.115 g (0.32 mmol) of the productof Step 4 and 0.092 g (0.45 mmol) of 2,6-di-tert-butyl-4-methylpyridinein 1.5 mL of dry dichloromethane was added 65 mL (0.39 mmol) oftrifluoromethanesulfonic anhydride under a nitrogen atmosphere at roomtemperature. After stirring under nitrogen for an additional 45 minutes,the reaction mixture was partitioned between ethyl acetate and water.The organic layer was extracted, washed with 0.5N hydrochloric acid,water, and brine, dried (MgSO₄), filtered and evaporated. The residualoil was purified on a silica gel flash chromatography column eluted with75% ethyl acetate-hexane which after evaporation and drying in vacuoafforded 0.099 g (63%) of the product as an amorphous solid.

NMR (CDCl₃) δ0.98 (t, J=9 Hz, 3H), 1.74-1.86 (m, 2H), 2.68 (s, 3H), 2.82(t, J=10 Hz, 2H), 5.54 (s, 2H), 7.04 (d, J=6 Hz, 1H), 7.18-7.31 (m, 6H),7.33-7.41 (m, 1H), 7.59 (d, J=10 Hz, 1H), 8.20 (d, J=6 Hz, 1H).

MS (FAB) m/e 489 (MH⁺).

EXAMPLE 42

Step 1:5,7-Dimethyl-2-ethyl-3-[(2'-nitrobiphen-4-yl)methyl]-3H-imidazo[4,5-b]pyridine

To a solution of 0.199 g (1.13 mmol) of5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine in 5 mL of anhydrousdimethylformamide was added 0.050 g (1.25 mmol) of a 60% mineral oildispersion of sodium hydride. The reaction mixture was magneticallystirred under a nitrogen atmosphere for 30 minutes, at which point 0.365g (1.25 mmol) of 4-bromomethyl-2'-nitrobiphenyl was added as a solid.The reaction mixture was stirred an additional 1.5 hours at roomtemperature, then partitioned between ethyl acetate and water. Theorganic layer was extracted, washed with brine, dried (MgSO₄), filteredand evaporated. The residual oil was purified on a silica gel flashchromatography column eluted with 50% ethyl acetate-hexane, which afterevaporation of the pure fractions and drying in vacuo afforded 0.340 g(77%) of the product as a tan solid.

NMR (CDCl₃) δ1.31 (t, J=10 Hz, 3H), 2.58 (s, 3H), 2.62 (s, 3H), 2.78 (q,J=10 Hz, 2H), 5.48 (s, 2H), 6.88 (s, 1H), 7.14-7.24 (m, 4H), 7.34-7.38(m, 1H), 7.42-7.48 (m, 1H), 7.54-7.60 (m, 1H), 7.83(d, J=10 Hz, 1H).

MS (FAB) m/e 387 (MH⁺).

Step 2:3-(2'-Aminobiphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine

To a solution of 0.340 g (0.88 mmol) of the product of Step 1 in 15 mLof absolute ethanol was added 35 mg of 10% palladium on carbon catalystand the mixture was hydrogenated at 40 psi of hydrogen on a Parrapparatus. Reduction was complete after 1.5 hours and the reactionmixture was filtered and evaporated in vacuo to afford a tan solid(0.300 g, 95%) which was used in the subsequent step without furtherpurification.

NMR (CDCl₃) δ1.33 (t, J=10 Hz, 3H), 2.59 (s, 3H), 2.64 (s, 3H), 2.84 (q,J=10 Hz, 2H), 3.70 (br s, 2H), 5.48 (s, 2H), 6.70-6.82 (m, 2H), 6.90 (s,1H), 7.03-7.22 (m, 4H), 7.36 (d, J=10 Hz, 2H).

MS (FAB) m/e 357 (MH⁺).

Step 3:5,7-Dimethyl-2-ethyl-3-(2'-trifluoromethylsulfonamido-biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To a magnetically stirred solution of 0.300 g (0.84 mmol) of the productof Step 2 and 0.190 g (0.93 mmol) of 2,6-di-tert-butyl-4-methylpyridinein 5.0 mL of dichloromethane was added 156 mL (0.93 mmol) oftrifluoromethanesulfonic anhydride under a nitrogen atmosphere at 0° C.The reaction was stirred under a nitrogen atmosphere for 1 hour while itslowly warmed to room temperature, then the mixture was partitionedbetween ethyl acetate and water. The organic layer was extracted, washedwith 0.5N hydrochloric acid, water, and brine, dried (MgSO₄), filteredand evaporated. The residual oil was purified on a silica gel flashchromatography column eluted with ethyl acetate to afford thesemi-purified product. The concentrated fractions were rechromatographedon silica gel eluted with 5% methanol-chloroform which after evaporationand drying in vacuo afforded 0.090 g (22%) of the product as anamorphous solid.

NMR (CDCl₃) δ1.33 (t, J=10 Hz, 3H), 2.58 (s, 3H), 2.63 (s, 3H), 2.79 (q,J=10 Hz, 2H), 5.51 (s, 2H), 6.89 (s, 1H), 7.21-7.31 (m, 6H), 7.34-7.40(m, 1H), 7.58 (d, J=11 Hz, 1H).

MS (FAB) m/e 489 (MH⁺).

EXAMPLE 43

Step 1: 2'-Methylbiphenyl-4-carboxylic acid methyl ester

A 2 L three-necked 24/40 round-bottom flask equipped with a mechanicalstirrer, a 500 mL constant pressure addition funnel with a nitrogeninlet at the top, and a septum was flame dried, cooled and then chargedwith a solution of 70.00 g (0.409 mol) of o-bromotoluene in 350 mL ofanhydrous tetrahydrofuran under a nitrogen atmosphere. The solution wasstirred and cooled to -78° C. and 481 mL (0..818 mol) of a 1.7M solutionof t-butyllithium in pentane was added via the addition funnel over 45minutes. When the addition was complete, the cooling bath was removedand the reaction mixture was stirred for 45 minutes and allowed to warmto room temperature. The dropping funnel was next charged with 409 mL(0.409 mol) of a 1.0M solution of zinc chloride in diethylether whichwas added to the reaction mixture over a 20 minute period. A separate 2L three-necked 24/40 round-bottom flask equipped with a mechanicalstirrer, a nitrogen inlet and a septum, was flame dried, cooled and thencharged with 8.93 g (13.7 mmol) of bis(triphenylphosphine)nickel(II)chloride, 58.71 g (0.273 mol) of methyl-2-bromobenzoate and 450 mL ofanhydrous tetrahydrofuran under a nitrogen atmosphere. The suspension ofthe tolylzinc chloride was then transferred to the second flask via awide diameter cannula. The reaction mixture was stirred an additional 45minutes at room temperature, then most of the tetrahydrofuran wasremoved on a rotary evaporator. The resulting oil was partitionedbetween ethyl acetate (500 mL) and water (300 mL). The organic layer waswashed successively with water, 5% hydrochloric acid, water, and brine,then dried (MgSO₄), filtered and evaporated. The residual oil waspurified on a Waters Prep 500 HPLC (2 silica packs) eluted with 1.5%ethyl acetate-hexane in eleven separate runs (mixed fractions recycled,10 g per injection). The purified fractions were evaporated and freed ofresidual solvent in vacuo to afford 53.42 g (74%) of a colorless oilwhich had.

NMR (CDCl₃) δ2.25 (s, 3H), 3.93 (s, 3H), 7.19-7.28 (m, 4H), 7.39 (d,J=12 Hz, 2H), 8.08 (d, J=12 Hz, 2H); MS (FAB) m/e (MH⁺).

Step 2: 2'-Bromomethylbiphenyl-4-carboxylic acid methyl ester

A 5 L three-necked 24/40 round-bottom flask equipped with a mechanicalstirrer, a reflux condenser with a nitrogen inlet at the top, and athermometer was charged with 53.42 g (0.204 mol) of 2'-methylbiphenyl-4-carboxylic acid methyl ester, 3.4 L carbon tetrachloride,38.09 g (0.214 mol) of N-bromosuccinimide and 2.0 g of2,2'-azobis(2-methylpropionitrile). The flask was degassed and flushedwith nitrogen, the stirrer was started and the contents were refluxedfor 5 hours. The reaction mixture was then cooled to room temperature,filtered and evaporated. The residual oil was purified byrecrystallization from dichloromethane-hexane to afford 48.48 g (78%) ofthe product which had.

mp 80°-81° C.

NMR (CDCl₃) δ3.94 (s, 3H), 4.40 (s, 2H), 7.20-7.26 (m, 1H), 7.32-7.41(m, 2H), 7.48-7.54 (m, 3H), 8.12 (d, J=12 Hz, 2H).

MS (EI) m/e 304, 306 (M⁺).

Anal. (C₁₅ H₁₃ BrO₂) C, H.

Step 3: 2'-[(Aminoiminomethyl)thio]methylbiphenyl-4-carboxylic acidmethylester, hydrobromide

To a solution of 4.120 g (54.1 mmol) of thiourea in 80 mL absoluteethanol was added a solution of 15.01 g (49.2 mmol) of2'-bromomethylbiphenyl-4-carboxylic acid methyl ester in 25 mL absoluteethanol and the mixture was magnetically stirred and refluxed for 4hours. After cooling to room temperature, a portion of the product whichhad crystallized during the reaction was isolated by filtration. Theremainder of the product was crystallized from the filtrate by additionof diethyl ether, filtered, and the combined product was dried in vacuoto afford 17.108 g (91%) of the isothiouronium salt which had: mp233°-234° C.

MS (FAB) m/e 301 (MH⁺ -Br).

Step 4: 2'-(N-t-Butylsulfonamido)methylbiphenyl-4-carboxylic acid methylester

A 500 mL 24/40 round-bottom flask charged with a suspension of 7.58 g(19.9 mmol) of the product of Step 3 in 175 mL glacial acetic acid and25 mL water was magnetically stirred at 0° C. and treated with a streamof chlorine gas introduced through a capillary pipet. After 20 min thechlorination was stopped, and the homogeneous yellow-green solution wasdiluted with 500 mL water. The oily layer which separated was extractedinto diethyl ether. The organic layer was washed with water, 5% aqueoussodium thiosulfate, brine, then dried (MgSO₄), filtered and evaporated.The residual oil was crystallized from diethyl ether-hexane and brieflydried in vacuo to afford the sulfonyl chloride: MS (EI) m/e 324 (M⁺).The sulfonyl chloride was then dissolved in 20 mL dichloromethane andwas slowly added to a stirred solution of 10 mL (95.0 mmol) oftert-butylamine in 20 mL of dichloromethane. After stirring 20 minutesat room temperature, the reaction mixture was partitioned betweendichloromethane and water. The organic layer was washed with 1Nhydrochloric acid and water, dried (MgSO₄), filtered and evaporated. Theproduct was purified on a silica gel flash chromatography column elutedwith 25% ethyl acetate-hexane to afford 5.050 g (70%) of the sulfonamideas a viscous oil which had:

NMR (CDCl₃) δ1.16 (s, 9H), 3.94 (s, 3H), 4.28 (s, 2H), 7.24-729 (m, 1H),7.36-7.43 (m, 2H), 7.45 (d, J=12 Hz, 1H), 7.64-7.70 (m, 1H), 8.08 (d,J=12 Hz, 1H); MS (EI) m/e 361 (M⁺).

Step 5: 2-N-t-Butylsulfoamidomethyl-4-hydroxymethylbiphenyl

To a magnetically stirred solution of 5.050 g (14.0 mmol) of thesulfonamide-ester (Step 4) in 25 mL anhydrous tetrahydrofuran was slowlyadded 18 mL (18.0 mmol) of a 1.0M solution of lithium aluminum hydridein tetrahydrofuran via syringe at room temperature under a nitrogenatmosphere. The reaction mixture was stirred for 5 hours at roomtemperature. At this point the excess reducing agent was decomposed bydropwise addition of water. The resulting suspension was diluted withethyl acetate, and the aqueous layer was acidified with concentratedhydrochloric acid until the precipitated salts were redissolved. Theorganic layer was then extracted and separated, washed with water,brine, dried (MgSO₄), filtered and evaporated. The residual oil waspurified on a silica gel flash chromatography column eluted with 75%ethyl acetate-hexane, and after evaporation of the fractions and dryingin vacuo afforded 2.282 g (49%) of the product as a viscous oil whichhad:

NMR (CDCl₃) δ1.15 (s, 9H), 1.56 (s, 1H), 3.87 (s, 1H), 4.32 (s, 2H),4.74 (br s, 2H), 7.24-7.28 (m, 1H), 7.34-7.45 (m, 6H), 7.64-7.69 (m,1H).

MS (EI) m/e 333 (M⁺).

Step 6: 2-N-t-Butylsulfonamido-4'-iodomethylbiphenyl

A dry 15 mL 14/20 round-bottom equipped with a magnetic stir bar and aseptum was charged sequentially with 1.162 g (3.49 mmol) of the productof Step 5, 7.0 mL of dichloromethane, 0.73 mL (5.23 mmol) oftriethylamine, and stirred at 0° C. under a nitrogen atmosphere.Methanesulfonyl chloride (0.33 mL, 4.18 mmol) was added slowly viasyringe and the reaction mixture was then stirred for 30 minutes. Thereaction mixture was then partitioned between dichloromethane and water;the organic layer was separated, dried (MgSO₄), filtered and evaporated.The residual oil was then redissolved in 3.0 mL of acetone, magneticallystirred at room temperature and treated with a solution of 1.045 g (7.0mmol) of sodium iodide in 10 mL of acetone. After stirring for 15minutes, the reaction mixture was concentrated in vacuo and the residuewas partitioned between ethyl acetate and water. The organic layer wasthen separated, washed with 5% sodium thiosulfate solution, brine, dried(MgSO₄), filtered, evaporated and dried in vacuo to afford 1.486 g (96%)of the iodide as a viscous oil which had:

NMR (CDCl₃) δ1.14 (s, 9H), 3.87 (br s, 1H), 4.30 (s, 2H), 4.48 (s, 2H),7.24-7.32 (m, 3H), 7.34-7.46 (m, 4H), 7.64-7.68 (m, 1H).

MS (EI) m/e 443 (M⁺).

Step 7:3-(2'-N-t-Butylsulfonamidomethylbiphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine

To a solution of 0.587 g (3.35 mmol) of7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine in 8.0 mL of anhydrousdimethylformamide was added 0.161 g (4.02 mmol) of a 60% mineral oildispersion of sodium hydride and the resultant reaction mixture wasstirred under a nitrogen atmosphere for 30 minutes at room temperature.At this point, a solution of 1.486 g (3.35 mmol) of the product of Step6 in 2.0 mL of anhydrous dimethylformamide was transferred to thereaction mixture via cannula. The reaction mixture was stirred anadditional 45 minutes at room temperature and then was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith water, brine, dried (MgSO₄), filtered, and evaporated. The residualoil was purified on a silica gel flash chromatography column eluted withethyl acetate. Evaporation of the appropriate fractions and drying invacuo, afforded 0.982 g (60%) of the product as a viscous oil which had:

NMR (CDCl₃) δ0.98 (t, J=10 Hz, 3H), 1.11 (s, 9H), 1.82 (m, 2H), 2.67 (s,3H), 2.84 (t, J=10 Hz, 2H), 3.88 (s, 1H), 4.24 (s, 2H), 5.51 (s, 2H),7.02 (d, J=8 Hz, 1H), 7.14-7.24 (m, 3H), 7.26-7.37 (m, 4H), 7.60-7.65(m, 1H), 8.18 (d, J=8 Hz, 1H).

MS (EI) m/e 490 (M⁺).

Step 8:7-Methyl-2-propyl-3-(2'-sulfonamidomethylbiphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To a solution of 0.982 g (2.00 mmol) of the product of Step 7 in 2.0 mLof dichloromethane was added 2.0 mL of trifluoroacetic acid and thereaction mixture was stirred under a nitrogen atmosphere for 16 hours atroom temperature. The reaction mixture was then concentrated in vacuoand the residue was purified on a silica gel flash chromatography columneluted with 80% ethyl acetate-hexane. After concentration of thepurified fractions and drying in vacuo 0.835 g (96%) of the primarysulfonamide as an amorphous solid was obtained which had:

NMR (CDCl₃) δ1.02 (t, J=10 Hz, 3H), 1.76-1.88 (m, 2H), 2.74 (s, 3H),3.08 (t, J=10 Hz, 2H), 4.29 (s, 2H), 4.63 (br s, 2H), 5.63 (s, 2H),7.17-7.40 (m, 8H), 7.58-7.64 (m, 1H), 8.33 (d, J=8 Hz, 1H); MS (EI) m/e434 (M⁺).

Step 9:3-(2'-(N-Acetyl)sulfonamidomethylbiphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine

To a solution of acetic anhydride (0.5 mL) and pyridine (0.5 mL) wasadded 0.034 g (0.078 mmol) of the product of Step 8 and the resultingmixture was magnetically stirred under a nitrogen atmosphere at roomtemperature for 16 hours. The reaction mixture was evaporated in vacuoand the residue was purified on a silica gel flash chromatography columneluted with ethyl acetate. Evaporation of the purified fractions anddrying in vacuo afforded 0.018 g (49%) of the product as a white foamwhich had:

NMR (CDCl₃) δ1.03 (t, J=10 Hz, 3H), 1.94 (m, 2H), 2.05 (s, 3H), 2.86 (s,3H), 3.21 (t, J=10 Hz, 2H), 4.55 (s, 2H), 5.66 (s, 2H), 7.16-7.38 (m,8H), 7.46-7.49 (m, 1H), 8.47 (d, J=8 Hz, 1H), 8.92 (br s, 1H).

MS (EI) m/e 476 (M⁺).

EXAMPLE 445-Bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]-pyridine

Step 1: 5-Chloro-2-ethyl-7-methylimidazo[4,5-b]pyridine

A solution of 2-ethyl-7-methylimidazo[4,5-b]pyridine (28 g, 174 mmol)and m-chloroperbenzoic acid (80-90%, 44.6 g) in CHCl₃ (300 mL) washeated at reflux for 0.5 hours. The mixture was concentrated andpurified (SiO₂, 100% CH₂ Cl₂ gradient to 30% CH₂ Cl₂ /MeOH) to give 29.8g of 2-ethyl-7-methylimidazo[4,5-b]pyridine-4-oxide as a solid.

¹ H NMR (300 MHz, CD₃ OD) δ8.13 (d, 1H, J=6 Hz), 7.13 (d, 1H, J=6 Hz),3.01 (q, 2H, J=7.5 Hz), 2.60 (s, 3H), 1.46 (t, 3H, J=7.5 Hz).

A mixture of the N-oxide (29.75 g, 0.168 mol), CHCl₃ (25 mL) and POCl₃(160 mL) was heated to 80° C. for 1 hours. After pouring over ice, themixture was neutralized by careful addition of NH₄ OH and extracted withEtOAc. Concentration gave 23.8 g of5-chloro-2-ethyl-7-methylimidazo[4,5-b]pyridine as a solid.

¹ H NMR (250 MHz, CDCl₃) δ7.07 (s, 1H) 3.10 (q, 2H, J=7.5 Hz), 2.67 (s,3H), 1.48 (t, 3H, J=7.5 Hz).

Step 2: 5-Bromo-2-ethyl-7-methylimidazo[4,5-b]pyridine

A mixture of the above stated chloride (22.2 g, 0.113 mol) in 30%HBr-HOAc was heated to 100° C. for 19 hours. The mixture was poured ontoice, neutralized with NH₄ OH, extracted (5×EtOAc), and the organiclayers were concentrated to give 15 g (1^(st) crop) of the bromide as asolid after crystallization from EtOAc.

¹ H NMR (300 MHz, CDCl₃) δ7.22 (s, 1H) 3.13 (q, 2H, J=7.5 Hz), 2.66 (s,3H), 1.47 (t, 3H, J=7.5 Hz).

Step 3:5-Bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo-[4,5-b]pyridine

The title compound was prepared according to the procedure described inExample 7 from 5-bromo-2-ethyl-7-methylimidazo[4,5-b]pyridine.

¹ H NMR (300 MHz, CD₃ OD) δ7.68-7.62 (m, 2H), 7.57-7.50 (m, 2H), 7.31(s, 1H), 7.13-7.05 (m, 4H), 5.51 (s, 2H), 2.87 (q, 2H, J=7.5 Hz), 2.62(s, 3H), 1.26 (t, 3H, J=7.5 Hz).

EXAMPLE 455-Chloro-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared according to the procedure described inExample 7 from 5-chloro-2-ethyl-7-methylimidazo[4,5-b]pyridine.

¹ H NMR (300 MHz, CD₃ OD) δ7.65-7.59 (m, 2H), 7.57-7.49 (m, 2H), 7.17(s, 1H), 7.10 (apparent s, 4H), 5.50 (s, 2H), 2.86 (q, 2H, J=7.5 Hz),2.63 (s, 3H), 1.26 (t, 3H, J=7.5 Hz).

EXAMPLE 465-Cyano-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

A mixture of5-bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(41 mg), CuCN (80 mg), and pyridine (0.2 mL) was heated with stirring to160° C. for 4 hours. The pyridine distilled off during the course of theheating. The cooled dark mass was dissolved in 2 mL of 20% aqueous KCNby heating to 50° C. for 15 minutes. Acetic acid (2 mL) (Caution! HCN isevolved.) was added and the mixture was extracted (2×EtOAc). The organiclayers were dried (Na₂ SO₄), concentrated, and purified (SiO₂, 80/20/1CH₂ Cl₂ --MeOH--NH₄ OH) to give 26 mg of the title compound as a solid.

¹ H NMR (250 MHz, CD₃ OD) δ7.66-7.45 (m, containing a singlet at 7.57,5H), 7.15-7.04 (m, 4H), 5.53 (s, 2H), 2.91 (q, 2H, J=7.5 Hz), 2.66 (s,3H), 1.27 (t, 3H, J=7.5 Hz).

EXAMPLE 475-Carboxy-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To neat5-Cyano-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(20 mg) at RT was added H₂ SO₄ (0.5 mL) and water (0.25 mL). The mixturewas heated to 100° C. for 3 hours, cooled to 0° C., then made basic bythe addition of NH₄ OH. After adding methanol (5 mL), the mixture wasfiltered, concentrated, and purified (SiO₂, 60:40:1 CH₂ Cl₂ --CH₃OH--NH₄ OH) to give 17 mg of the title compound as a solid.

FAB MS (M⁺ +1)=440.

¹ H NMR (300 MHz, CD₃ OD) δ7.90 (s, 1H), 7.56-7.39 (m, 4H), 7.05(apparent s, 4H), 5.62 (s, 2H), 2.86 (q, 2H, J=7.5 Hz), 2.67 (s, 3H),1.26 (t, 3H, J=7.5 Hz).

EXAMPLE 485-(Ethoxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo-[4,5-b]pyridine

Dry HCl was bubbled through a slurry of5-carboxy-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(200 mg) in EtOH (50 mL) for 30 seconds. The mixture became homogeneousand was stirred for 18 hour at RT. Concentration, neutralization (NH₄OH), partitioning between dilute aqueous HOAc and EtOAc followed byevaporation of the organic layer gave 220 mg of the title compound as asolid.

¹ H NMR (300 MHz, CD₃ OD) δ7.94 (s, 1H), 7.63-7.56 (m, 2H), 7.51(apparent t, 2H, J=8 Hz), 7.12-7.03 (AB quartet, 4H), 5.62 (s, 2H), 4.44(q, 2H, J=7.2 Hz), 2.86 (q, 2H, J=7.5 Hz), 2.70 (s, 3H), 1.43 (t, 3H,J=7.2 Hz), 1.27 (t, 3H, J=7.5 Hz).

EXAMPLE 492-Ethyl-5-(methoxycarbonyl)-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo-[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 48.

¹ H NMR (300 MHz, CD₃ OD) δ7.98 (s, 1H), 7.68-7.62 (m, 2H), 7.54(apparent t, 2H, J=8 Hz), 7.16-7.06 (AB quartet, 4H), 5.66 (s, 2H), 3.99(s, 3H), 2.91 (q, 2H, J=7.5 Hz), 2.71 (s, 3H), 1.28 (t, 3H, J=7.5 Hz).

EXAMPLE 505-(Benzyloxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo-[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 48.

FAB MS (M⁺ +1)=530.

¹ H NMR (300 MHz, CD₃ OD) δ7.96 (s, 1H), 7.58-7.33 (m, 9H), 7.12-7.03(AB quartet, 4H), 5.60 (s, 2H), 5.44 (s, 2H), 2.90 (q, 2H, J=7.5 Hz),2.68 (s, 3H), 1.28 (t, 3H, J=7.5 Hz).

EXAMPLE 512-Ethyl-5-(iso-propyloxycarbonyl)-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo-[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 48.

FAB MS (M⁺ +1)=482.

¹ H NMR (300 MHz, CD₃ OD) δ7.93 (s, 1H), 7.57-7.38 (m, 4H), 7.07 (s,4H), 5.61 (s, 2H), 5.29 (quintet, 1H, J=6.3 Hz), 2.89 (q, 2H, J=7.5 Hz),2.69 (s, 3H), 1.42 (d, 2H, J=6.3 Hz), 1.27 (t, 3H, J=7.5 Hz).

EXAMPLE 525-(n-Butyloxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 48.

¹ H NMR (300 MHz, CD₃ OD) δ7.92 (s, 1H), 7.61 (t, 2H, J=7.6 Hz),7.55-7.45 (m, 2H), 7.18-7.03 (AB quartet, 4H), 5.62 (s, 2H), 4.38 (t,2H, J=6.6 Hz), 2.89 (q, 2H, J=7.5 Hz), 2.67 (s, 3H), 1.84-1.73 (m, 2H),1.59-1.43 (m, 2H), 1.26 (t, 3H, J=7.5 Hz), 0.99 (t, 3H, J=7.5 Hz).

EXAMPLE 535-Carboxamido-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To5-Cyano-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(22 mg) at RT was added 0.63 mL of 0.5N aqueous NaOH, MeOH (0.3 mL), andH₂ O₂ (0.018 mL). After stirring for 16 hours the solution wasevaporated and purified (SiO₂, 80/20/1 CH₂ Cl₂ /MeOH/NH₄ OH) to give 20mg solid.

¹ H NMR (300 MHz, CD₃ OD) δ7.91 (s, 1H), 7.58-7.41 (m, 4H), 7.12-7.03(AB quartet, 4H), 5.58 (s, 2H), 2.89 (q, 2H, J=7.5 Hz), 2.68 (s, 3H),1.27 (t, 3H, J=7.5 Hz).

EXAMPLE 542-Ethyl-7-methyl-5-(morpholin-4-yl)carbonoyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To5-(ethoxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(30 mg) in THF (1 mL) at RT was added 0.25 mL of morpholine and NaH (20mg of an 80% dispersion). After stirring for 16 hours, 1% aqueous HOAc(2 mL) was added. Extractive workup (EtOAc), and purification (SiO₂,75/25/1 CH₂ Cl₂ /MeOH/NH₄ OH) gave 10 mg of a solid.

¹ H NMR (300 MHz, CD₃ OD) δ7.62-7.52 (m, 2H), 7.50-7.42 (m, 2H), 7.40(s, 1H), 7.06 (s, 4H), 5.52 (s, 2H), 3.82-3.72 (m, 4H), 3.58-3.46 (m,4H), 2.94 (q, 2H, J=7.5 Hz), 2.69 (s, 3H), 1.30 (t, 3H, J=7.5 Hz)

EXAMPLE 552-Ethyl-7-methyl-5-(isopropyl)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To5-bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo-[4,5-b]pyridine(75 mg) in THF (2 mL) at -78° C. was sequentially added ZnCl₂ (1.58 mL,1M/ether), iso-propylmagnesium chloride (0.79 mL, 2M/ether), andtetrakis-triphenylphosphinepalladium (15 mg). After complete additionthe reaction was warmed to RT and stirred for 16 hours. Extractiveworkup (EtOAc, from dilute HOAc), and purification (SiO₂, 80/20/1 CH₂Cl₂ /MeOH/NH₄ OH) gave 43 mg of a solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.60-7.50 (m, 2H), 7.45 (t, 2H, J=6.9 Hz),7.12-7.00 (m, 5H), 5.50 (s, 2H), 3.10 (quintet, 1H, J=6.9 Hz) 2.84 (q,2H, J=7.5 Hz), 2.59 (s, 3H), 1.31 (d, 6H, J=6.9 Hz), 1.24 (t, 3H, J=7.5Hz).

EXAMPLE 565-Ethyl-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo]4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 55.

¹ H NMR (300 MHz, CD₃ OD) δ7.64-7.43 (m, 4H), 7.12-7.00 (m, 5H), 5.52(s, 2H), 2.90-2.78 (m, 4H), 2.58 (s, 3H), 1.35-1.19 (m, 6H).

EXAMPLE 572-Ethyl-5-(n-hexyl)-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 55.

¹ H NMR (300 MHz, CD₃ OD) δ7.60 (t, 2H J=7.8 Hz) 7.54-7.44 (m, 2H),7.14-7.03 (m, 4H), 7.06 (s, 1H), 5.53 (s, 2H), 2.90-2.78 (m, 4H), 2.59(s, 3H), 1.78-1.64 (m, 2H), 1.40-1.24 (m, 6H), 1.24 (t, 3H), J=7.5 Hz),0.86 (t, 3H, J=6 Hz).

EXAMPLE 582-Ethyl-7-methyl-5-phenyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 55.

¹ H NMR (300 MHz, CD₃ OD) δ8.07 (d, 2H, J=7.2 Hz), 7.63 (s, 1H),7.58-7.34 (m, 7H), 7.16-7.04 (m, 4H), 5.56 (s, 2H), 2.89 (q, 2H, J=7.5Hz), 2.69 (s, 3H), 1.29 (t, 3H, J=7.5 Hz).

EXAMPLE 592-Ethyl-7-methyl-5-(tetrazol-5-yl)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

A mixture of5-Cyano-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(54 mg), trimethylstannyl azide (79 mg), toluene (5 mL), and DMF (1 mL)was heated to 110° C. for 24 hour. Concentration and purification (SiO₂,70/30/1 CH₂ Cl₂ /MeOH/NH₄ OH) gave 47 mg solid.

¹ H NMR (300 MHz, CD₃ OD) δ7.93 (s, 1H), 7.56-7.38 (m, 4H), 7.14-7.05(AB quartet, 4H), 5.61 (s, 2H), 2.86 (q, 2H, J=7.5 Hz), 2.71 (s, 3H),1.27 (t, 3H, J=7.5 Hz)

EXAMPLE 605-Acetyl-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To5-Cyano-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(137 mg) at 0° C. in THF (5 mL) was added methylmagnesium bromide (0.70mL, 3M/ether). After stirring for 6 hour, 10% aqueous HOAc was added,the mixture was heated to 50° C. for 10 minutes then extracted withEtOAc. Purification (SiO₂, 93/3/4 CH₂ Cl₂ /MeOH/HOAc) gave 40 mg of thetitle compound.

¹ H NMR (300 MHz, CD₃ OD) δ7.88 (s, 1H), 7.67-7.60 (m, 2H), 7.58-7.50(m, 2H), 7.28-7.05 (AB quartet, 4H), 5.63 (s, 2H), 2.95 (q, 2H, J=7.5Hz), 2.70 (s, 3H), 2.68 (s, 3H), 130 (t, 3H, J=7.5 Hz)

EXAMPLE 612-Ethyl-5-((RS)-1-hydroxy)ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To5-acetyl-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(25 mg) in MeOH (1 mL) at 0° C. was added NaBH₄ (50 mg). After 0.5hours, 1% aqueous HOAc (2 mL) was added. Extractive workup (EtOAc), andpurification (SiO₂, 93/3/4 CH₂ Cl₂ /MeOH/HOAc) gave 25 mg of the titlecompound.

¹ H NMR (300 MHz, CD₃ OD) δ7.58 (t, 2H, J=7.5 Hz), 7.48 (t, 2H, J=7.5Hz), 7.27 (s, 1H), 7.14-7.02 (AB quartet, 4H), 5.54 (s, 2H), 4.94 (q,1H, J=6.6 Hz), 2.85 (q, 2H, J=7.5 Hz), 2.63 (s, 3H), 1.51 (d, 3H, J=6.6Hz), 1.24 (t, 3H, J=7.5 Hz).

EXAMPLE 622-Ethyl-5-(hydroxymethyl)-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To5-(ethoxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(50 mg) in THF (1 mL) at -78° C. was added Diisobutylaluminum hydride(0.534 mL, 1M/THF). After 1 hour at -78° C., the mixture was warmed toRT and 1% aqueous HOAc (2 mL) was added. Extractive workup (EtOAc), andpurification (SiO₂, 80/20/1 CH₂ Cl₂ /MeOH/NH₄ OH) gave 28 mg of a solid.

¹ H NMR (300 MHz, CD₃ OD) δ7.57 (t, 2H, J=7.5 Hz), 7.48 (t, 2H, J=7.5Hz), 7.26 (s, 1H), 7.08-7.02 (AB quartet, 4H), 5.54 (s, 2H), 4.74 (s,2H), 2.85 (q, 2H, J=7.5 Hz), 2.66 (s, 3H), 1.26 (t, 3H, J=7.5 Hz).

EXAMPLE 632-Ethyl-5-(2-hydroxyprop-2-yl)-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To5-(ethoxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(43 mg) at -78° C. in THF (1 mL) was added methylmagnesium bromide (0.77mL, 3M/ether). Extractive workup (EtOAc, from aqueous NH₄ Cl) andpurification (SiO₂, 93/3/4 CH₂ Cl₂ /MeOH/HOAc) gave 20 mg of the titlecompound.

¹ H NMR (300 MHz, CD₃ OD) δ7.56-7.40 (m, 4H), 7.39 (s, 1H), 7.24-7.04(AB quartet, 4H), 5.50 (s, 2H), 2.87 (q, 2H, J=7.5 Hz), 2.64 (s, 3H),1.59 (s, 6H), 1.27 (t, 3H, J=7.5 Hz)

EXAMPLE 642-Ethyl-5-(3-hydroxypent-3-yl)-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 63.

¹ H NMR (300 MHz, CD₃ OD) δ7.65-7.59 (m, 2H), 7.51 (m, 2H), 7.30 (s,1H), 7.20-7.02 (AB quartet, 4H), 5.50 (s, 2H), 2.90 (q, 2H, J=7.5 Hz),2.65 (s, 3H), 2.07-1.79 (m, 4H), 1.27 (t, 3H, J=7.5 Hz), 0.68 (t, 6H,J=7.2 Hz).

EXAMPLE 655-Amino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

A mixture of5-Bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine.(2.0 g), and hydrazine hydrate (15 mL) was heated to 120° C. for 24hours. Concentration and purification (SiO₂, 85/14/2 CH₂ Cl₂ /MeOH/NH₄OH) gave 1.80 g of5-hydrazino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine.Reduction in methanol (50 mL) under 1 atm. H₂ with W-2 Raney nickle (1mL, 50% dispersion/water) at RT for 48 hours gave the title compound(1.44 g) after purification (SiO₂, 85/14/2 CH₂ Cl₂ /MeOH/NH₄ OH).

¹ H NMR (300 MHz, CD₃ OD) δ7.60-7.50 (m, 2H), 7.49-7.42 (m, 2H),7.10-7.00 (m, 4H), 6.38 (s, 1H), 5.39 (s, 2H), 2.79 (q, 2H, J=7.5 Hz),2.49 (s, 3H), 1.21 (t, 3H, J=7.5 Hz).

EXAMPLE 665-Amino-2-ethyl-7-(trifluoromethyl)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To a mixture of 2,6-diamino-4-trifluoromethylpyridine (173 mg) in H₂ SO₄(3 mL) at 0° C. was added HNO₃ (0.048 mL, d=1.40). The stirred mixturewas sequentially warmed to RT, aged 1.5 hours, poured onto 50 g ice,neutralized with NH₄ OH, extracted with EtOAc, filtered through 20 gSiO₂ (washed with EtOAc until yellow color eluted), and concentrated togive 70 mg of 2,6-diamino-3-nitro-4-trifluoromethylpyridine as a yellowsolid. A 1:1 THF/MeOH solution of the nitro compound (65 mg) washydrogenated (1 atm H₂, Ra-Ni, 16 hours at RT), filtered, concentrated,and converted to the title compound by the method outlined in Example21.

FAB MS (M⁺ +1)=465.

¹ H NMR (300 MHz, CD₃ OD) δ7.61 (t, 2H, J=7.8 Hz), 7.54-7.48 (m, 2H),7.13-7.04 (AB q, 4H), 6.74 (s, 1H), 5.41 (s, 2H), 2.79 (q, 2H, J=7.5Hz), 1.16 (t, 3H, J=7.5 Hz).

EXAMPLE 672-Ethyl-5-(methylamino)-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

A mixture of5-Bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(74 mg), methylamine (0.6 g), and EtOH (2 mL) was heated in a bomb at180° C. for 16 hours. Concentration and purification (SiO₂, 90/9/1 CH₂Cl₂ /MeOH/NH₄ OH) gave 34.4 mg of the title compound.

¹ H NMR (300 MHz, CD₃ OD) δ7.60-7.51 (m, 2H), 7.49-7.42 (m, 2H),7.17-7.05 (m, 4H), 6.33 (s, 1H), 5.44 (s, 2H), 2.90 (s, 3H), 2.79 (q,2H, J=7.8 Hz), 2.47 (s, 3H), 1.22 (t, 3H, J=7.8 Hz).

EXAMPLE 685-(Dimethylamino)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 67.

¹ H NMR (300 MHz, CD₃ OD) δ7.60-7.52 (m, 2H), 7.51-7.44 (m, 2H),7.18-7.05 (AB q, 4H), 6.52 (s, 1H), 5.45 (s, 2H), 3.12 (s, 6H), 2.88 (q,2H, J=7.8 Hz), 2.54 (s, 3H), 1.24 (t, 3H, J=7.8 Hz).

EXAMPLE 695-(Methylamino)-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 20.

¹ H NMR (300 MHz, CD₃ OD) δ7.69-7.55 (m, 3H), 7.55-7.45 (m, 2H),7.20-7.03 (AB q, 4H), 6.52 (d, 1H J=8.7 Hz), 5.47 (s, 2H), 2.92 (s, 3H),2.82 (t, 2H, J=7.3 Hz), 1.78-1.62 (m, 2H), 0.96 (t, 3H, J=7.4 Hz).

EXAMPLE 705-(Dimethylamino)-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 20.

¹ H NMR (300 MHz, CD₃ OD) δ7.67 (d, 1H, J=9 Hz), 7.60-7.40 (m, 4H),7.18-7.00 (AB q, 4H), 6.63 (d, 1H J=9 Hz), 5.40 (s, 2H), 3.10 (s, 6H),2.78 (t, 2H, J=7.5 Hz), 1.73-1.59 (m, 2H), 0.93 (t, 3H, J=7.4 Hz).

EXAMPLE 712-Ethyl-5-(hexylamino)-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 67.

¹ H NMR (300 MHz, CD₃ OD) δ7.57-7.48 (m, 2H), 7.48-7.38 (m, 2H),7.15-7.02 (AB q, 4H), 6.28 (s, 1H), 5.38 (s, 2H), 3.33-3.28 (m, 2H),2.80 (q, 2H, J=7.5 Hz), 2.45 (s, 3H), 1.68-1.55 (m, 2H), 1.45-1.25 (m,8H), 1.21 (t, 3H, J=7.5 Hz),.0.87 (t, 3H, J=7.0 Hz).

EXAMPLE 725-(2-Aminoethyl)amino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a method similar to thatdescribed in Example 67.

¹ H NMR (300 MHz, CD₃ OD) δ7.67 (d, 1H, J=6.6 Hz), 7.49-7.39 (m, 3H),7.07 (d, 2H, J=8 Hz), 6.89 (d, 2H, J=8 Hz), 6.33 (s, 1H), 5.45 (s, 2H),3.55 (t, 2H J=5 Hz), 3.12 (t, 2H J=5 Hz), 2.89 (q, 2H, J=7.8 Hz), 2.50(s, 3H), 1.31 (t, 3H, J=7.8 Hz).

EXAMPLE 735-(Carboxymethyl)amino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 67.

¹ H NMR (300 MHz, CD₃ OD) δ7.53-7.35 (m, 4H), 7.08-7.00 (AB q, 4H), 6.28(s, 1H), 5.35 (s, 2H), 3.89 (s, 2H), 2.74 (q, 2H, J=7.5 Hz), 2.49 (s,3H), 1.20 (t, 3H, J=7.5 Hz).

EXAMPLE 742-Ethyl-7-methyl-5-(4-morpholino)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 67.

¹ H NMR (300 MHz, CD₃ OD) δ7.65-7.58 (m, 2H), 7.51 (t, 2H J=7.2 Hz),7.17-7.05 (AB q, 4H), 6.67 (s, 1H), 5.45 (s, 2H), 3.81 (t, 2H J=5 Hz),3.53 (t, 2H, J=5 Hz), 2.87 (q, 2H, J=7.5 Hz), 2.56 (s, 3H), 1.24 (t, 3H,J=7.5 Hz).

EXAMPLE 752-Ethyl-7-methyl-5-(methylthio)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 67.

¹ H NMR (300 MHz, CD₃ OD) δ7.68-7.61 (m, 2H), 7.51 (t, 2H J=7.8 Hz),7.19-7.03 (AB q, 4H), 7.00 (s, 1H), 5.52 (s, 2H), 2.87 (q, 2H, J=7.8Hz), 2.58 (s, 6H), 1.26 (t, 3H, J=7.8 Hz).

EXAMPLE 762-Ethyl-5-hydroxy-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 67.

¹ H NMR (300 MHz, CD₃ OD) δ7.61-7.52 (m, 2H), 7.51-7.43 (m, 2H), 7.06(apparent s, 4H), 6.44 (s, 1H), 5.41 (s, 2H), 2.80 (q, 2H, J=7.5 Hz),2.55 (s, 3H), 1.22 (t, 3H, J=7.5 Hz).

EXAMPLE 775-Ethoxy-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 67.

¹ H NMR (300 MHz, CD₃ OD) δ7.64-7.57 (m, 2H), 7.55-7.47 (m, 2H),7.17-7.04 (AB q, 4H), 6.52 (s, 1H), 5.45 (s, 2H), 4.35 (q, 2H, J=7.2Hz), 2.86 (q, 2H, J=7.8 Hz), 2.56 (s, 3H), 1.37 (t, 3H, J=7.2 Hz), 1.22(t, 3H, J=7.8 Hz).

EXAMPLE 785-(Acetamidoethyl)amino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To5-(2-aminoethyl)amino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(20 mg) in THF (1 mL) at °C. was added AcCl (3.4 μL) and triethylamine(18 μL). After 1 h, the solvent was evaporated and the residue waspurified (SiO₂, 80:20:1 CHCl₃, MeOH, NH₄ OH) to give 17 mg of the titlecompound.

¹ H NMR (300 MHz, CD₃ OD) δ7.63-7.45 (m, 4H), 7.18-7.04 (AB q, 4H), 6.33(s, 1H), 5.43 (s, 2H), 3.47 (t, 2H J=5 Hz), 3.38 (t, 2H J=5 Hz), 2.86(q, 2H, J=7.8 Hz), 2.47 (s, 3H), 1.90 (s, 3H), 1.22 (t, 3H, J=7.8 Hz).

EXAMPLE 792-Ethyl-5-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 16.

¹ H NMR (300 MHz, CDCl₃) δ785 (d, 1H, J=8 Hz), 7.59-7.47 (m, 2H), 7.31(dd, 1H, J=7.2, 1.8 Hz), 7.16 (d, 1H, J=8 Hz), 6.92-6.74 (AB q, 4H),5.32 (s, 2H), 2.54 (s, 3H), 2.52 (q, 2H), 1.12 (t, 3H).

EXAMPLE 805-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 16.

¹ H NMR (300 MHz, CD₃ OD) δ787 (d, 1H, J=8 Hz), 7.69-7.58 (m, 2H),7.59-7.49 (m,2H), 7.20 (d, 1H, J=8 Hz), 7.09 (apparent singlet, 4H),5.57 (s, 2H), 2.80 (q, 2H, J=7.5 Hz), 2.63 (s, 3H), 0.96 (t, 3H, J=7.5Hz).

EXAMPLE 816-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 16.

¹ H NMR (300 MHz, CD₃ OD) δ8.20 (s, 1H), 7.82 (s, 1H), 7.63-7.54 (m,2H), 7.52-7.44 (m, 2H), 7.07 (apparent singlet, 4H), 5.53 (s, 2H), 2.82(t, 2H, J=7.5 Hz), 2.48 (s, 3H), 1.80-1.75 (m, 2H), 0.96 (t, 3H, J=7.5Hz).

EXAMPLE 826-Bromo-7-methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 10 Step 1 and Example 7.

¹ H NMR (300 MHz, acetone-D6) δ8.35 (s, 1H), 7.78 (d, 1H), 7.68-7.48 (m,4H), 7.18-7.08 (ABq, 4H), 5.55 (s, 2H), 2.85 (t, 2H, J=7.5 Hz), 2.67 (s,3H), 1.80-1.75 (m, 2H), 0.98 (t, 3H, J=7.5 Hz).

EXAMPLE 837-Ethyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

tert-Butyllithium (0.978 mL, 1.7M/pentane) was added to a cooled (-78°C.) THF (5 mL) solution of 7-methyl-2-propylimidazo[4,5-b]pyridine (97mg, 0.554 mmol). After 2 hour the reaction was warmed to 0° C. for 1minute then cooled back to -78° C. MeI (0.172 mL) was added, the mixturewas stirred at -78° C. for 1 hour then warmed to 0° C. for 1 minute andthen quenched (NH₄ OH). Extractive workup and purification (SiO₂, 2%MeOH/ EtOAc) gave 85 mg of 7-ethyl-2-propylimidazo[4,5-b]pyridine whichwas converted to the title compound as outlined in Example 7, Part B.

¹ H NMR (250 MHz, CD₃ OD) δ8.28 (d, 1H, J=6 Hz), 7.72-7.65 (m, 2H),7.62-7.54 (m, 2H), 7.22 (d, 1H, J=6 Hz), 7.17-7.08 (AB q, 4H), 5.61 (s,2H), 3.12 (q, 2H, J=9 Hz), 2.89 (t, 2H, J=9 Hz), 1.80-1.63 (m, 2H), 1.41(t, 3H, J=9 Hz), 0.99 (t, 3H, J=9 Hz).

EXAMPLE 847-Isopropyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

7-Isopropyl-2-propylimidazo[4,5-b]pyridine was prepared from7-ethyl-2-propylimidazo[4,5-b]pyridine by the metallation-alkylationsequence described in the first part of Example 83. The title compoundwas prepared by using a similar method to that described in Example 7,Part B.

¹ H NMR (300 MHz, CDCl₃) δ8.11 (d, 1H, J=5 Hz), 7.88 (dd, 1H, J=7.5, 1.5Hz), 7.58-7.46 (m, 2H), 7.37-7.32 (m, 1H), 7.04 (d, 1H, J=5 Hz),7.03-6.85 (AB q, 4H), 5.37 (s, 2H), 3.48-3.34 (m, 1H), 2.56 (t, 2H,J=7.2 Hz), 1.76-1.62 (m, 2H), 1.22 (d, 6H, J=6.6 Hz), 0.92 (t, 3H, J=7.2Hz).

EXAMPLE 857-Ethyl-2-ethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 83.

¹ H NMR (250 MHz, CD₃ OD) δ8.21 (d, 1H, J=5 Hz), 7.56-7.37 (m, 4H), 7.15(d, 1H, J=5 Hz), 7.09-6.97 (AB q, 4H), 5.53 (s, 2H), 3.08 (q, 2H, J=8Hz), 2.88 (q, 2H, J=7.5 Hz), 1.38 (t, 3H, J=7.5 Hz), 1.26 (t, 3H, J=7.5Hz).

EXAMPLE 866-Hydroxymethyl-7-methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

To a cooled (-78° C.) stirred solution of2-propyl-6-bromo-7-methylimidazo[4,5-b]pyridine (540 mg, 2.15 mmol) inTHF (20 mL) was added tert-butyl-lithium (4.40 mL, 1.7M/pentane) over 30seconds After 45 minutes, dimethylformamide (0.665 mL) was added andafter 10 additional minutes the reaction was warmed to RT and quenchedwith 20% aqueous 4 NH₄ Cl. Extractive workup EtOAc (4×10 mL) andpurification (SiO₂, 4% MeOH/EtOAc) gave2-propyl-7-methylimidazo[4,5-b]pyridine-6-carboxaldehyde (350 mg). To astirred, cooled (0° C.) methanolic (15 mL) solution of the aldehyde (300mg) was added NaBH₄ (84 mg). After 30 minutes HOAc (0.1 mL) was added,the mixture was warmed (RT), concentrated, and purified (SiO₂, 10%MeOH/CH₂ Cl₂) to give 190 mg of6-hydroxymethyl-7-methyl-2-propylimidazo[4,5-b]pyridineas an oil. Thetitle compound was prepared by using a similar method to that describedin Example 7, Part B.

¹ H NMR (300 MHz, CD₃ OD) δ8.25 (s, 1H), 7.59-7.41 (m, 4H), 7.18-7.09(ABq, 4H), 5.52 (s, 2H), 4.79 (s, 2H), 2.83 (t, 2H, J=7.5 Hz), 2.70 (s,3H), 1.78-1.63 (m, 2H), 0.96 (t, 3H, J=7.5 Hz).

EXAMPLE 872-Propyl-7-(p-tolyl)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 55.

¹ H NMR (300 MHz, CDCl₃) δ7.95-7.84 (m, 3H), 7.62-7.49 (m, 3H),7.43-7.33 (m, 2H), 7.28-7.22 (m, 2H), 6.98-6.93 (AB q, 4H), 5.45 (s,2H), 2.49 (t, 2H, J=7.5 Hz), 2.38 (s, 3H), 1.68-1.54 (m, 2H), 0.83 (t,3H, J=7.5 Hz).

EXAMPLE 882-Propyl-7-methyl-6-(p-tolyl)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 55.

¹ H NMR (300 MHz, CDCl₃) δ8.13 (s, 1H), 7.64-7.54 (m, 2H), 7.54-7.44 (m,2H), 7.32-7.24 (m, 2H), 7.16-7.04 (m, 6H), 5.57 (s, 2H), 2.87 (t, 2H,J=7.5 Hz), 2.57 (s, 3H), 2.42 (s, 3H), 1.78-1.65 (m, 2H), 0.99 (t, 3H,J=7.5 Hz).

EXAMPLE 895-Chloro-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared starting with5-chloro-2,3-pyridinediamine by using a similar method to that describedin Example 9.

¹ H NMR (300 MHz, 1:1 CD₃ OD/CDCl₃) δ7.90 (d, 1H, J=8.4 Hz), 7.64-7.39(m, 4H), 7.24 (d, 1H, J=8.4 Hz), 7.10-7.00 (ABq, 4H), 5.44 (s, 2H), 2.73(t, 2H, J=7.5 Hz), 1.81-1.67 (m, 2H), 0.94 (t, 3H, J=7.5 Hz).

EXAMPLE 906-Amino-5,7-dimethyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared starting with3,5,6-triamino-2,4-lutidine by using a similar method to that describedin Example 20.

¹ H NMR (300 MHz, CD₃ OD) δ7.62-7.52 (m, 2H), 7.52-7.42 (m, 2H), 7.06,(s, 4H), 5.53 (s, 2H), 2.85 (t, 2H, J=7.5 Hz), 2.53 (s, 3H), 2.45 (s,3H), 1.72-1.55 (m, 2H), 0.93 (t, 3H, J=7.5 Hz).

EXAMPLE 917-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine-4-oxide

A solution of7-Methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(9 mg) and m-chloroperoxybenzoic acid (6 mg) CHCl₃ (2 mL) was heated toreflux for 2 hours. Concentration and purification (SiO2, 80:20:1 CH₂Cl₂ /MeOH/NH₄ OH) gave 4 mg of the title compound as a solid.

¹ H NMR (300 MHz, CD₃ OD) δ8.07 (d, 1H, J=6 Hz), 7.60-7.43 (m, 4H),7.19, (d, 1H, J=6 Hz), 7.09 (s, 4H), 6.14 (s, 2H), 2.82 (t, 2H, J=7.5Hz), 2.63 (s, 3H), 1.81-1.67 (m, 2H), 0.98 (t, 3H, J=7.5 Hz).

EXAMPLE 925,7-Dimethyl-6-hydroxy-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound can be prepared by diazotization of6-Amino-5,7-dimethyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl]-3H-imidazo[4,5-b]pyridinein conc. HCl with 1 equiv of NaNO₂ at RT followed by heating to 80° C.for 2 hours and subsequent neutralization (NH₄ OH), extraction, andpurification.

EXAMPLE 935,7-Dimethyl-2-(3,3,3-trifluoroprop-2-yl)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared in a manner similar to Example 16.

FAB MS (M⁺ +1)=478.

EXAMPLE 942-(3-Butyn-1-yl)-5,7-dimethyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared in a manner similar to Example 16. R_(f)=0.52. (tlc, Merck Kieselgel 60 F-254, 40/10/1 CHCl₃ MeOH NH₄ OH).

EXAMPLE 955,7-Dimethyl-2-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared in a manner similar to Example 16.

FAB MS (M⁺ +1)=396.

¹ H NMR (300 MHz, CD₃ OD) δ7.62-7.53 (m, 2H), 7.52-7.44 (m, 2H),7.08-7.00 (AB q, 4H), 7.02 (s, 1H), 5.51 (s, 2H), 2.58 (s, 3H), 2.50 (s,3H).

EXAMPLE 967-Chloro-2-ethyl-5-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 44, Step 1, and Example 45 starting with5-methyl-2-ethylimidazo[4,5-b]pyridine.

¹ H NMR (300 MHz, CD₃ OD) δ7.68-7.56 (m, 2H), 7.58-7.48 (m, 2H), 7.26(s, 1H), 7.10 (s, 4H), 5.55 (s, 2H), 2.86 (q, 2H, J=7.5 Hz), 2.61 (s,3H), 1.25 (t, 3H, J=7.5 Hz).

EXAMPLE 972-Ethyl-5-methyl-7-(4-morpholino)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared starting with7-chloro-2-ethyl-5-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridineby using a similar method to that described in Example 67.

¹ H NMR (300 MHz, CD₃ OD) δ7.60-7.50 (m, 2H), 7.50-7.42 (m, 2H),7.12-6.90 (ABq, 4H) 6.51 (s, 1H), 5.45 (s, 2H), 3.95-3.78 (m, 8H), 2.74(q, 2H, J=7.5 Hz), 2.50 (s, 3H), 1.22 (t, 3H, J=7.5 Hz).

EXAMPLE 982-Ethyl-5-methyl-7-(methylamino)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 96.

¹ H NMR (300 MHz, CD₃ OD) δ7.58-7.49 (m, 2H), 7.49-7.40 (m, 2H),7.11-6.90 (ABq, 4H) 6.37 (s, 1H), 5.45 (s, 2H), 3.04 (s, 3H), 2.75 (q,2H, J=7.5 Hz), 2.51 (s, 3H), 1.26 (t, 3H, J=7.5 Hz).

EXAMPLE 997-(Dimethylamino)-2-ethyl-5-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 96.

¹ H NMR (300 MHz, CD₃ OD) δ7.58-7.39 (m, 4H), 7.13-6.87 (ABq, 4H) 6.36(s, 1H), 5.45 (s, 2H), 3.46 (s, 6H), 2.73 (q, 2H, J=7.5 Hz), 2.49 (s,3H), 1.25 (t, 3H, J=7.5 Hz).

EXAMPLE 1002-Ethyl-5-methyl-7-(methylthio)-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared by using a similar method to thatdescribed in Example 75.

¹ H NMR (300 MHz, CD₃ OD) δ7.55-7.38 (m, 4H), 7.18-6.95 (ABq, 4H) 7.00(s, 1H), 5.49 (s, 2H), 2.81 (q, 2H, J=7.5 Hz), 2.62 (s, 3H), 2.60 (s,3H), 1.22 (t, 3H, J=7.5 Hz).

EXAMPLE 1015,7-Dimethyl-2-ethyl-3-(4'-chloro-2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

Step 1: 2-Cyano-4-nitro-4'-methylbiphenyl

To a solution of p-tolyltrimethyltin (389 mg, 1.525 mmol) in dry toluene(5 mL) under N₂ was added 2-bromo-5-nitro-benzonitrile (276 mg, 1.22mmol) and Pd(PPh₃)₄ (176 mg; 10 mol %). The reaction was stirred atreflux under N₂ for 24 hours and then cooled to room temperature. Themixture was diluted with EtOAc and the solid was removed by filtrationthrough a pad of celite. The filtrate was concentrated in vacuo and theresidue was purified by flash chromatography on a silica column elutingwith Hex/EtOAc (10:1) to afford 214 mg (74%) of the titled compound as aslightly yellow solid.

¹ H NMR (300 MHz, CDCl₃) δ2.42 (s, 3H), 7.32 (d, 2H), 7.48 (d, 2H), 7.69(d, 1H), 8.45 (dd, 1H), 8.61 (s, 1H).

Step 2: N-Triphenylmethyl-5-(4'-methyl-4-nitrobiphen-2-yl)tetrazole

The titled compound was prepared starting from2-cyano-4-nitro-4'-methylbiphenyl (step 1) according to proceduresdescribed in European Patent Application EP 0,291,969.

¹ H NMR (300 MHz, CDCl₃) δ2.28 (s, 3H), 6.89 (d, 6H), 6.98 (ABq, 4H),7.22-7.37 (comp, 9H), 7.56 (d, 1H), 8.31 (dd, 1H), 8.75 (d, 1H).

Step 3: N-Triphenylmethyl-5-(4-chloro-4'-methylbiphen-2-yl)tetrazole

A solution ofN-Triphenylmethyl-5-(4'-methyl-4-nitrobiphen-2-yl)tetrazole (0.115 g,0.224 mmol) in MeOH/DMF (2 mL/12 mL) was submitted to hydrogenation at40 psi H₂ with 10% Pd on carbon (50 mg) at room temperature for 1 hour.The reaction was filtered through celite and the filtrate wasconcentrated in vacuo. The triphenyl methyl group had been lost duringthe hydrogenation. The crude 4-amino compound was dissolved in glacialacetic acid (3 mL) and added slowly to a cooled (0° C.) solution ofNaNO₂ (28.8 mg, 0.417 mmol) in conc. sulfuric acid (1 mL). The diazoniumsolution was stirred well for 2 hoursr then slowly added to a cooled (0°C.) solution of CuCl (0.449 g; 20 equiv) in conc. HCl. This mixture wasstirred for 30 minutes and then poured over H₂ O and extracted withEt20/EtOAc. The combined organic extracts were washed with H₂ O andbrine, dried over MgSO4 and concentrated in vacuo. The product waspurified by flash chromatography on a silica column eluting withHex/EtOAc/HOAc (80:20;1) to afford 27 mg (45% for 2 steps) of5-(4-chloro-4'-methyl-biphen-2-yl)tetrazole. The free tetrazole wasdissolved in CH₂ Cl₂ (3.5 mL) and NEt₃ (0.035 mL, 2.5 equiv) and Ph₃ CCl(27 mg, 1.0 equiv) were added. After 30 minutes the reaction was dilutedwith Et₂ O washed with 10% citric acid, 1N NaOH and brine. The organicwas dried over anhydrous MgSO₄ and concentrated in vacuo to afford 51.2mg (100%) of crudeN-triphenylmethyl-5-(4-chloro-4'-methyl-biphen-2-yl)tetrazole.

¹ H NMR (300 MHz, CDCl₃) δ2.26 (s, 3H), 6.91 (d, 6H), 6.94 (ABq, 4H),7.20-7.25 (comp, 7H), 7.43 (dd, 1H), 7.99 (dd, 1H).

Step 4:N-Triphenylmethyl-5-(4'-bromomethyl-4-chlorobiphen-2-yl)tetrazole

The titled compound was prepared starting fromN-Triphenylmethyl-5-(4-chloro-4'-methyl-biphen-2-yl)tetrazole (step 1 to3) according to procedures described in European Patent Application EP0,291,969.

Step 5:5,7-Dimethyl-2-ethyl-3-(4'-chloro-2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared from5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine andN-triphenylmethyl-5-(4'-bromomethyl-4-chlorobiphen-2-yl)tetrazole in amanner similar to Example 7, and was isolated as an HCl salt.

¹ H NMR (300 MHz, CD₃ OD) δ1.38 (t, 3H), 2.72 (s, 6H), 3.28 (q, 2H),5.82 (s, 2H), 7.18 (d, 2H), 7,36 (d, 2H), 7.44 (s, 1H), 7.58 (d, 1H),7.72 (dd, 1H), 7.76 (d, 1H).

FAB mass spectrum, m/e 444 (M+H, calcd for C₂₄ H₂₂ N₇ Cl, 444).

EXAMPLE 1025,7-Dimethyl-2-ethyl-3-(4'-fluoro-2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]-pyridine

Table I shows intermediates that were used to make this and otherangiotensin II antagonists in a manner similar to Example 102.

EXAMPLE 1035-(Acetoxymethyl)-2-ethyl-7-methyl-3-(2'-tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine

A mixture of2-Ethyl-5-(hydroxymethyl)-7-methyl-3-((2'-tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(34 mg), acetic anhydride (0.25 mL), and triethylamine (0.5 mL) in CH₂Cl₂ (2 mL) was stirred at rt for 3 hours. Extractive (EtOAc) work upfrom dilute aqueous HOAc and purification (SiO₂, 80/20/1 CH₂ Cl₂/MeOH/NH₄ OH) gave 30 mg of the title compound.

FAB MS: M+1=468.

¹ H NMR (300 MHz, CD₃ OD) δ7.66-7.57 (m, 2H), 7.55-7.46 (m, 2H), 7.19(s, 1H), 7.13-7.02 (AB quartet, 4H), 5.53 (s, 2H), 5.23 (s, 2H), 2.86(q, 2H, J=7.5 Hz), 2.63 (s, 3H), 2.11 (s, 3H), 1.25 (t, 3H, J=7.5 Hz).

EXAMPLE 104 Typical Pharmaceutical Compositions Containing a Compound ofthe Invention

A: Dry Filled Capsules Containing 50 mg of Active Ingredient Per Capsule

    ______________________________________                                        Ingredient    Amount per capsule (mg)                                         ______________________________________                                        7-methyl-2-propyl-3-                                                                         50                                                             (2'-(tetrazol-5-yl)                                                           biphen-4-yl)methyl-                                                           3H-imidazo[4,5-b]                                                             pyridine                                                                      Lactose       149                                                             Magnesium stearate                                                                           1                                                              Capsule (size No. 1)                                                                        200                                                             ______________________________________                                    

The7-methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridinecan be reduced to a No. 60 powder and the lactose and magnesium stearatecan then be passed through a No. 60 blotting cloth onto the powder. Thecombined ingredients can then be mixed for about 10 minutes and filledinto a No. 1 dry gelatin capsule.

B: Tablet

A typical tablet would contain7-methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(25mg), pregelatinized starch USP (82 mg), microcrystaline cellulose (82mg) and magnesium stearate (1 mg).

C: Combination Tablet

A typical combination tablet would contain, for example, a diuretic suchas hydrochlorothiazide and consist of (7.5 mg), hydrochlorothiazide (50mg) pregelatinized starch USP (82 mg), microcrystalline cellulose (82mg) and magnesium stearate (1 mg).

D: Suppository

Typical suppository formulations for rectal administration can contain7-methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(1-25 mg), butylated hydroxyanisole (0.08-1.0 mg), disodium calciumedetate (0.25-0.5 mg), and polyethylene glycol (775-1600 mg). Othersuppository formulations can be made by substituting, for example,butylated hydroxytoluene (0.04-0.08 mg) for the disodium calcium edetateand a hydrogenated vegetable oil (675-1400 mg) such as Suppocire L,Wecobee FS, Wecobee M, Witepsols, and the like, for the polyethyleneglycol. Further, these suppository formulations can also include anotheractive ingredient such as another antihypertensive and/or a diureticand/or an angiotensin converting enzyme and/or a calcium channel blockerin pharmaceutically effective amounts as described, for example, in Cabove.

E: Injection

A typical injectible formulation would contain7-methyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine(5.42 mg), sodium phosphate dibasic anhydrous (11.4 mg) benzyl alcohol(0.01 ml) and water for injection (1.0 ml). Such as injectibleformulation can also include a pharmaceutically effective amount ofanother active ingredient such as another antihypertensive and/or adiuretic and/or an angiotensin converting enzyme inhibitor and/or acalcium channel blocker.

What is claimed is:
 1. A compound of structural formula: ##STR49##wherein: R¹ is(a) --CO₂ R⁴, (b) --SO₃ R⁵, (c) --NHSO₂ CF₃, (d)--PO(OR⁵)₂, (e) --SO₂ --NH--R⁹, (f) --CONHOR⁵, (g) ##STR50## (h) --SO₂NH-heteroaryl, (i) --CH₂ SO₂ NH-heteroaryl, (j) --SO₂ NHCO--R²³, (k)--CH₂ SO₂ NHCO--R²³, (l) --CONH--SO₂ R²³, (m) --CH₂ CONH--SO₂ R²³, (n)--NHSO₂ NHCO--R²³, (o) --NHCONHSO₂ --R²³, (p) --SO₂ NHCONR²³, (q)##STR51## (r) ##STR52## (s) ##STR53## (t) --CONHNHSO₂ CF₃, (u) ##STR54##(v) ##STR55## (w) ##STR56## wherein heteroaryl is an unsubstituted,monosubstituted or disubstituted five- or six-membered aromatic ringwhich can optionally contain 1 to 3 heteroatoms selected from the groupconsisting of O, N or S and wherein the substituents are membersselected from the group consisting of --OH, --SH, --C₁ -C₄ -alkyl, --C₁-C₄ -alkoxy, halo, --NO₂, --CO₂ H, --CO₂ --C₁ -C₄ -alkyl, --NH₂, --NH(C₁-C₄ -alkyl) and --N(C₁ -C₄ -alkyl)₂ ; R^(2a) and R^(2b) areindependently H, halo, --NO₂, --NH₂, C₁ -C₄ -alkylamino, di(C₁ -C₄alkyl)amino, --SO₂ NHR⁹, CF₃, C₁ -C₄ -alkyl, or C₁ -C₄ -alkoxy; R^(3a)is(a) H, (b) halo (c) C₁ -C₆ -alkyl, (d) C₁ -C₆ -alkoxy, (e) C₁ -C₆-alkoxyalkyl; R^(3b) is(a) H, (b) halo (c) NO₂, (d) C₁ -C₆ -alkyl, (e)C₁ -C₆ -acyloxy, (f) C₁ -C₆ -cycloalkyl (g) C₁ -C₆ -alkoxy, (h) --NHSO₂R⁴, (i) hydroxy C₁ -C₄ -alkyl, (j) aryl C₁ -C₄ -alkyl (k) C₁ -C₄-alkylthio (l) C₁ -C₄ -alkyl sulfinyl (m) C₁ -C₄ -alkyl sulfonyl (n) NH₂(o) C₁ -C₄ -alkylamino (p) C₁ -C₄ -dialkylamino (q) fluoro C₁ -C₄ -alkyl(r) --SO₂ --NHR⁹ (s) aryl or, (t) furyl; wherein aryl is phenyl ornaphthyl optionally substituted with one or two substituents selectedfrom the group consisting of halo, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, NO₂,CF₃, C₁ -C₄ -alkylthio, OH, NH₂, NH(C₁ -C₄ -alkyl), N(C₁ -C₄ -alkyl)₂,CO₂ H, and CO₂ --C₁ -C₄ -alkyl; R⁴ is H, straight chain or branched C₁-C₆ alkyl, aryl or --CH₂ -aryl where aryl is as defined above; R^(4a) isC₁ -C₆ -alkyl, aryl or --CH₂ -aryl where aryl is as defined above; R⁵ isH, ##STR57## E is a single bond, --NR¹³ (CH₂)_(s) --, --S(O)_(x) --(CH₂)_(s) -- where x is 0 to 2 and s is 0 to 5, --CH(OH)--, --O--,--CO--; R⁶ is(a) aryl as defined above optionally substituted with 1 or2 substituents selected from the group consisting of halo --O--C₁ -C₄-alkyl, C₁ -C₄ -alkyl, --NO₂, --CF₃, --SO₂ NR⁹ R¹⁰, --S--C₁ -C₄ -alkyl,--OH, --NH₂, C₃ -C₇ -cycloalkyl, C₃ -C₁₀ -alkenyl; (b) straight chain orbranched C₁ -C₉ -alkyl, C₂ -C₆ -alkenyl or C₂ -C₆ -alkynyl each of whichcan be optionally substituted with a substituent selected from the groupconsisting of aryl as defined above, C₃ -C₇ -cycloalkyl, halo --OH,--NH₂, --NH(C₁ -C₄ -alkyl), --CF₂ CF₃, --N(C₁ -C₄ -alkyl)₂, --NH--SO₂R⁴, --COOR⁴, --CF₃, --CF₂ CH₃, --SO₂ NHR⁹ ; or (c) an unsubstituted,monosubstituted or disubstituted aromatic 5 or 6 membered ring whichcontains one or two members selected from the group consisting of N, O,S, and wherein the substituents are members selected from the groupconsisting of --OH, --SH, C₁ -C₄ -alkyl, C₁ -C₄ -alkyloxy--CF₃, halo, orNO₂, (d) perfluoro-C₁ -C₄ -alkyl, (e) C₃ -C₇ -cycloalkyl optionallymono- or disubstituted with C₁ -C₄ -alkyl or --CF₃ ; R⁹ is H, C₁ -C₅-alkyl, aryl or --CH₂ -aryl where aryl is as defined above; R¹⁰ is H, C₁-C₄ -alkyl; R¹¹ is H, C₁ -C₆ -alkyl, C₂ -C₄ -alkenyl, C₁ -C₄ -alkoxy-C₁-C₄ -alkyl, or ##STR58## R¹² is --CN, --NO₂ or --CO₂ R⁴ ; R¹³ is H,--CO(C₁ -C₄ -alkyl), C₁ -C₆ -alkyl, allyl, C₃ -C₆ -cycloalkyl, phenyl orbenzyl; R¹⁴ is H, C₁ -C₈ -alkyl, C₁ -C₈ -perfluoroalkyl, C₃ -C₆-cycloalkyl, phenyl or benzyl; R¹⁵ is H, C₁ -C₆ -alkyl; R¹⁶ is H, C₁ -C₆-alkyl, C₃ -C₆ -cycloalkyl, phenyl or benzyl; R¹⁷ is --NR⁹ R¹⁰, --OR¹⁰,--NHCONH₂, --NHCSNH₂, ##STR59## R¹⁸ and R¹⁹ are independently C₁ -C₄-alkyl or taken together are --(CH₂)_(q) -- where q is 2 or 3; R²⁰ is H,--NO₂, --NH₂, --OH or --OCH₃ ; R²³ is(a) aryl as defined above, (b)heteroaryl as defined above, (c) C₃ -C₄ -cycloalkyl, (d) C₁ -C₄ -alkylwhich can be optionally substituted with a substituent that is a memberselected from the group consisting of aryl as defined above, heteroarylas defined above, --OH, --SH, --C₁ -C₄ -alkyl, --O(C₁ -C₄ -alkyl),--S(C₁ -C₄ -alkyl), --CF₃, halo --NO₂, --CO₂ H, --CO₂ --C₁ -C₄ -alkyl,--NH₂, NH(C₁ -C₄ -alkyl), --NHCOR^(4a), --N(C₁ -C₄ -alkyl)₂, --PO₃ H,--PO(OH) (C₁ -C₄ -alkyl), --PO(OH) (aryl) or --PO(OH) (O--C₁ -C₄-alkyl), (e) perfluoro-C₁ -C₄ -alkyl; X is(a) a carbon-carbon singlebond, (b) --CO--, (c) --O--, (d) --S--, (e) ##STR60## (f) ##STR61## (g)##STR62## (h) --OCH₂ --, (i) --CH₂ O-- (j) --SCH₂ --, (k) --CH₂ S--, (l)--NHC(R⁹)(R¹⁰)--, (m) --NR⁹ SO₂ --, (n) --SO₂ NR⁹ --, (o)--C(R⁹)(R¹⁰)NH--, (p) --CH═CH--, (q) --CF═CF--, (r) --CH═CF--, (s)--CF═CH--, (t) --CH₂ CH₂ --, (u) --CF₂ CF₂ --, (v) ##STR63## (w)##STR64## (x) ##STR65## (y) ##STR66## or (z) ##STR67## --A--B--C--D--represents ##STR68## R⁸ groups can be the same or different andrepresent: a) hydrogen, b) C₁ -C₆ -alkyl or alkenyl either unsubstitutedor substituted with hydroxy, C₁ -C₄ -alkoxy, --N(R⁴)₂, --CO₂ R⁴ or C₃-C₅ -cycloalkyl, c) C₃ -C₅ -cycloalkyl, with the proviso that both R⁸groups cannot be hydrogen;the pharmaceutically acceptable salts thereof.2. The compound of claim 1, wherein:R¹ is:a) --CO₂ R⁴ b) --NHSO₂ CF₃ c)##STR69## d) ##STR70## (e) --SO₂ NH-heteroaryl, (f) --CH₂ SO₂NH-heteroaryl, (g) --SO₂ NHCOR²³, (h) --CH₂ SO₂ NHCOR²³, (i) --CONHSO₂R²³, (j) --CH₂ CONHSO₂ R²³, (k) --NHSO₂ NHCOR²³, or (l) --NHCONHSO₂ R²³,(m) --SO₂ NHCONHR²³, wherein heteroaryl is as defined in claim 1; X is asingle bond; R^(2a) and R^(2b) are independently:a) C₁ -C₄ -alkyl, b)halogen, c) hydrogen; R^(3a) and R^(3b) are independently:a) C₁ -C₆-alkyl, b) halogen, or c) C₁ -C₆ -alkoxy, d) hydrogen; R⁴ is H, or C₁-C₄ -alkyl; E is a single bond or --S--; R⁶ is a branched or straightchain C₁ -C₆ -alkyl, C₃ -C₇ -cycloalkyl, C₂ -C₆ -alkenyl or C₂ -C₆-alkynyl each of which is either unsubstituted or substituted with C₁-C₄ -alkylthio, C₁ -C₄ -alkoxy, CF₃, CF₂ CF₃ or --CF₂ CH₃ ; and the R⁸groups are the same or different and represent,a) hydrogen, b) C₁ -C₄-alkyl either unsubstituted or substituted with --OH or --CO₂ R⁴ ; andwith the proviso that both R⁸ groups cannot be hydrogen.
 3. Apharmaceutical formulation for the treatment of hypertension andcongestive heart failure comprising a pharmaceutically acceptablecarrier and an effective antihypertensive amount of the compound ofclaim
 1. 4. A method of treating hypertension and congestive heartfailure comprising the administration of an effective antihypertensiveamount of the compound of claim 1 to a patient in need of suchtreatment.
 5. An ophthalmological formulation for the treatment ofocular hypertension comprising an ophthalmologically acceptable carrierand an effective ocular antihypertensive amount of a compound ofclaim
 1. 6. A method of treating ocular hypertension comprisingadministering to a patient in need of such treatment an effective ocularantihypertensive amount of a compound of claim 1.